Erfani M, etal., BMC Cancer. 2020 Apr 25;20(1):350. doi: 10.1186/s12885-020-6706-x.
BACKGROUND: ARID1A has been described as a tumor suppressor gene, participating in chromatin re-modeling, epithelial-mesenchymal-transition and many other cellular and molecular processes. It has been cited as a contribute in tumorigenesis. The role o
f ARID1A in CRC is not yet defined. AIM: To investigate the role of ARID1A methylation and CNV in its expression in CRC cell lines and to examine the relationship between ARID1A status with survival and clinicopathologic characteristics in patients with CRC. METHODS: We used RT-PCR to determine both CNV and expression of ARID1A from six CRC cell lines. We used MSP to evaluate methylation of ARID1A. IHC was used to assess ARID1A protein expression. We also evaluated MSI and EMAST status in 18 paired CRC and adjacent normal tissues. 5AzadC was used to assess effect of DNA demethylation on ARID1A expression. Statistical analysis was performed to establish correlations between ARID1A expression and other parameters. RESULTS: Among the 18 CRC tumors studied, 7 (38.8%) and 5 tumors (27.7%) showed no or low ARID1A expression, respectively. We observed no significant difference in ARID1A expression for overall patient survival, and no difference between clinicopathological parameters including MSI and EMAST. However, lymphatic invasion was more pronounced in the low/no ARID1A expression group when compared to moderate and high expression group (33% VS. 16.6% respectively. ARID1A promoter methylation was observed in 4/6 (66%) cell lines and correlated with ARID1A mRNA expression level ranging from very low in SW48, to more pronounced in HCT116 and HT-29/219. Treatment with the methyltransferase inhibitor 5-Azacytidine (5-aza) resulted in a 25.4-fold and 6.1-fold increase in ARID1A mRNA expression in SW48 and SW742 cells, respectively, while there was no change in SW480 and LS180 cells. No ARID1A CNV was observed in the CRC cell lines. CONCLUSION: ARID1A expression is downregulated in CRC tissues which correlates with it being a tumor suppressor protein. This finding confirms ARID1A loss of expression in CRC development. Our in-vitro results suggest high methylation status associates with reduced ARID1A expression and contributes to CRC tumorigenesis. However, there was no significant association between ARID1A loss of expression and clinicopathological characteristics. Future in-vivo analysis is warranted to further establish ARID1A role in colorectal neoplastic transformation.
The AT-rich interacting domaincontaining protein 1A gene (ARID1A) encodes ARID1A, a member of the SWI/SNF chromatin remodeling complex. Mutation of ARID1A induces changes in expression
of multiple genes (CDKN1A, SMAD3, MLH1 and PIK3IP1) via chromatin remodeling dysfunction, contributes to carcinogenesis, and has been shown to cause transformation of cells in association with the PI3K/AKT pathway. Information on ARID1A has emerged from comprehensive genomewide analyses with nextgeneration sequencers. ARID1A mutations have been found in various types of cancer and occur at high frequency in endometriosisassociated ovarian cancer, including clear cell adenocarcinoma and endometrioid adenocarcinoma, and also occur at endometrial cancer especially in endometrioid adenocarcinoma. It has also been suggested that ARID1A mutation occurs at the early stage of canceration from endometriosis to endometriosisassociated carcinoma in ovarian cancer and also from atypical endometrial hyperplasia to endometrioid adenocarcinoma in endometrial cancer. Therefore, development of a screening method that can detect mutations of ARID1A and activation of the PI3K/AKT pathway might enable early diagnosis of endometriosisassociated ovarian cancers and endometrial cancers. Important results may also emerge from a current clinical trial examining a multidrug regimen of temsirolimus, a small molecule inhibitor of the PI3K/AKT pathway, for treatment of advanced ovarian clear cell adenocarcinoma with ARID1A mutation and PI3K/AKT pathway activation. Also administration of sorafenib, a multikinase inhibitor, can inhibit cancer proliferation with PIK3CA mutation and resistance to mTOR inhibitors and GSK126, a moleculartargeted drug can inhibit proliferation of ARID1Amutated ovarian clear cell adenocarcinoma cells by targeting and inhibiting EZH2. Further studies are needed to determine the mechanism of chromatin remodeling dysregulation initiated by ARID1A mutation, to develop methods for early diagnosis, to investigate new cancer therapy targeting ARID1A, and to examine the involvement of ARID1A mutations in development, survival and progression of cancer cells.
AT-rich interactive domain 1A gene (ARID1A) loss is a frequent event in endometriosis-associated ovarian carcinomas. Endometriosis is a disease in which tissue that normally grows inside the uterus grows outside the uterus, and 50% of women with endometriosis a
re infertile. ARID1A protein levels were significantly lower in the eutopic endometrium of women with endometriosis compared to women without endometriosis. However, an understanding of the physiological effects of ARID1A loss remains quite poor, and the function of Arid1a in the female reproductive tract has remained elusive. In order to understand the role of Arid1a in the uterus, we have generated mice with conditional ablation of Arid1a in the PGR positive cells (Pgrcre/+Arid1af/f; Arid1ad/d). Ovarian function and uterine development of Arid1ad/d mice were normal. However, Arid1ad/d mice were sterile due to defective embryo implantation and decidualization. The epithelial proliferation was significantly increased in Arid1ad/d mice compared to control mice. Enhanced epithelial estrogen activity and reduced epithelial PGR expression, which impedes maturation of the receptive uterus, was observed in Arid1ad/d mice at the peri-implantation period. The microarray analysis revealed that ARID1A represses the genes related to cell cycle and DNA replication. We showed that ARID1A positively regulates Klf15 expression with PGR to inhibit epithelial proliferation at peri-implantation. Our results suggest that Arid1a has a critical role in modulating epithelial proliferation which is a critical requisite for fertility. This finding provides a new signaling pathway for steroid hormone regulation in female reproductive biology and furthers our understanding of the molecular mechanisms that underlie dysregulation of hormonal signaling in human reproductive disorders such as endometriosis.
Zhou H, etal., Mol Med Rep. 2019 Mar;19(3):2125-2136. doi: 10.3892/mmr.2019.9886. Epub 2019 Jan 22.
AT‑rich interaction domain 1A (ARID1A) and phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit α (PIK3CA) serve important roles in the formation and development of numerous malignancies including gastric cancer. Accumulating evidence has demon
strated that Epstein‑Barr virus (EBV) is a pathogenic virus associated with gastric cancer. The present study aimed to investigate the association between EBV infection, and the expression levels of ARID1A and PIK3CA in gastric cancer. EBER in situ hybridization was performed to detect EBV infection. Immunohistochemistry was used to assess the expression levels of ARID1A and PIK3CA in gastric cancer and adjacent normal tissues. A total of 58 gastric cancer and 10 adjacent normal tissues were tested for genetic mutations via single nucleotide polymorphism genotyping assays. Fluorescent polymerase chain reaction was used to detect EBV infection; 9.3% (28/300) of gastric cancer samples were positive for EBV, whereas, all adjacent normal tissues were negative. ARID1A and PIK3CA were negatively correlated in gastric cancer (r=‑0.167). The expression levels of ARID1A and PIK3CA in gastric cancer were significantly associated with the depth of invasion of gastric cancer. A total of 62.1% (36/58) of tumor samples exhibited mutations in ARID1A, whereas, 13.8% (8/58) presented mutations in PIK3CA. Notably, EBV‑associated gastric cancer (EBVaGC) samples with PIK3CA mutations additionally exhibited ARID1A mutations. Although in the present study it was identified that ARID1A and PIK3CA were negatively correlated in EBVaGC, further studies are required to investigate the association among ARID1A, PIK3CA and EBV in gastric cancer.
Wu Y, etal., Biomed Res Int. 2016;2016:7593787. doi: 10.1155/2016/7593787. Epub 2016 Jan 21.
ARID1A is one of the important cancer-related genes and regulates transcription of certain genes by altering chromatin structure. Inactivated mutations and decreased expression of ARID1A gene have been reported in several ki
nds of cancer. Histone H2B is a major component of chromatin and encoded by HIST1H2BE. The goal of the study is to evaluate expressing status of ARID1A and H2B as well as their correlation on breast cancer. Gene expression profiles of ARID1A and H2B on Oncomine database are analyzed. Tissue microarray of breast cancer was used for examination of ARID1A and H2B expression by immunohistochemistry. As a result, the disagreement of ARID1A expression was found, while HIST1H2BE expression is elevated in 4 out of 5 datasets on Oncomine database. There were 15 cases (20%) of breast cancers that were positive for ARID1A. Fifty-eight out of 75 cases of breast cancer (77.3%) were highly expressed for H2B protein and 17 cases (22.7%) were low expressed for H2B protein. All cases with ARID1A expression are overlapped with H2B high expression. Among 15 cases with ARID1A and H2B coexpression, 13 are invasive ductal carcinoma and 2 are mucinous carcinoma. Our results indicate that ARID1A gene may be involved in carcinogenesis of some subtypes of breast cancer.
ARID1A/BAF250a has been recently implicated as a tumor suppressor in gastric cancer. We sought to clarify the clinical significance of BAF250a/ARID1A in relation to other clinical parameters and relevant biomarkers in gastri
c carcinoma. Cases from 2 separate cohorts of patients with gastric carcinoma from Vancouver (n = 173) and Toronto (n = 80) were selected for the construction of tissue microarrays, which were used to assess the immunohistochemical status of BAF250a (anti-ARID1A), mismatch repair proteins and p53, as well as in situ hybridization for HER2 amplification and Epstein-Barr virus infection. The Toronto cohort contained a higher proportion of early stage cases (P = .019) and a smaller proportion of cases from the proximal stomach (P < .001). Overall, immunohistochemical loss of BAF250a was observed in 22.5% of gastric adenocarcinomas from the Vancouver group and 20% from Toronto. In both cohorts, loss of BAF250a was positively associated with loss of mismatch repair protein expression (P < .0001 and P = .035, respectively). Loss of BAF250a expression was independently associated with poor overall survival in the Toronto cohort (P = .0015), whereas no significant association with survival was observed in the Vancouver cohort. BAF250a loss was not significantly associated with any additional clinical parameters in either cohort. HER2 amplification was confirmed as a negative prognostic factor in both cohorts. These findings suggest that ARID1A/BAF250a may be of prognostic significance in a subset of patients with early stage gastric cancer and that pathological assessment should increasingly use a multimarker approach.
BACKGROUND/AIM: Gastric cancer is a common cancer worldwide. Chromatin remodeling complexes have emerged as tumor suppressors and include AT-rich interaction domain-containing proteins (ARIDs) 1A, 1B, and 2. We examined their expression and clarified their roles in gastric carcinogenesis.
MATERIALS AND METHODS: The expression of ARIDs was studied by immunohistochemistry in 469 gastric carcinoma and 47 adenoma samples and was analyzed according to clinicopathological factors. RESULTS: Low expression rates of ARID1A, 1B, and 2 in gastric carcinoma were 20%, 10%, and 15% respectively. ARIDs are correlated to each other. Low expression of ARID1A was related to advanced tumor and vessel infiltration. Loss of ARID1B and ARID2 was also related to tumor progression, but their relationship was weaker than that of ARID1A. CONCLUSION: ARID1A is the strongest tumor suppressor in gastric carcinogenesis among ARIDs. Their aberration might be caused by shared mechanisms such as mutation and methylation.
AT-rich interactive domain 1A (ARID1A) is one of the most frequently mutated genes in hepatocellular carcinoma (HCC), but its clinical significance is not clarified. We aimed to evaluate the clinical significance of low ARID1A
n> expression in HCC. By analyzing the gene expression data of liver from Arid1a-knockout mice, hepatic Arid1a-specific gene expression signature was identified (p < 0.05 and 0.5-fold difference). From this signature, a prediction model was developed to identify tissues lacking Arid1a activity and was applied to gene expression data from three independent cohorts of HCC patients to stratify patients according to ARID1A activity. The molecular features associated with loss of ARID1A were analyzed using The Cancer Genome Atlas (TCGA) multi-platform data, and Ingenuity Pathway Analysis (IPA) was done to uncover potential signaling pathways associated with ARID1A loss. ARID1A inactivation was clinically associated with poor prognosis in all three independent cohorts and was consistently related to poor prognosis subtypes of previously reported gene signatures (highly proliferative, hepatic stem cell, silence of Hippo pathway, and high recurrence signatures). Immune activity, indicated by significantly lower IFNG6 and cytolytic activity scores and enrichment of regulatory T-cell composition, was lower in the ARID1A-low subtype than ARID1A-high subtype. Ingenuity pathway analysis revealed that direct upstream transcription regulators of the ARID1A signature were genes associated with cell cycle, including E2F group, CCND1, and MYC, while tumor suppressors such as TP53, SMAD3, and CTNNB1 were significantly inhibited. ARID1A plays an important role in immune activity and regulating multiple genes involved in HCC development. Low-ARID1A subtype was associated with poor clinical outcome and suggests the possibility of ARID1A as a prognostic biomarker in HCC patients.
AIMS: The carcinogenesis of ovarian clear cell carcinoma (CCC) has been hypothesized to comprise two different pathways: an adenofibroma-carcinoma sequence and an endometriosis-carcinoma sequence. However, the difference in the genetic basis of these two pathways remains unclear. Recent studies hav
e suggested that an ARID1A mutation and the loss of the corresponding protein, BAF250a, are frequent events in CCC. Herein, we investigated the difference in the loss of BAF250a expression in adenofibroma-related CCC and endometriosis-related CCC. METHODS AND RESULTS: In total, 93 cases of surgically treated CCC were evaluated. The presence of adenofibroma and endometriosis associated with carcinoma was determined by reviewing haematoxylin and eosin-stained slides for each case. BAF250a expression in carcinoma was examined immunohistochemically. The loss of BAF250a expression was detected in carcinomas in 50 of 93 (54%) cases, including five of 18 (28%) with adenofibroma alone, 30 of 45 (67%) with endometriosis alone, eight of 18 (44%) with both conditions and seven of 12 (58%) with neither condition. The loss of BAF250a expression was significantly less frequent in CCC cases with adenofibroma than in cases with endometriosis (P = 0.01, Fisher's exact test). CONCLUSIONS: The action of ARID1A in carcinogenesis differs between adenofibroma-related CCC and endometriosis-related CCC.
Sun X, etal., Cancer Cell. 2017 Nov 13;32(5):574-589.e6. doi: 10.1016/j.ccell.2017.10.007.
ARID1A, an SWI/SNF chromatin-remodeling gene, is commonly mutated in cancer and hypothesized to be tumor suppressive. In some hepatocellular carcinoma patients, ARID1A was highly expressed in primary tumors but not in metast
atic lesions, suggesting that ARID1A can be lost after initiation. Mice with liver-specific homozygous or heterozygous Arid1a loss were resistant to tumor initiation while ARID1A overexpression accelerated initiation. In contrast, homozygous or heterozygous Arid1a loss in established tumors accelerated progression and metastasis. Mechanistically, gain of Arid1a function promoted initiation by increasing CYP450-mediated oxidative stress, while loss of Arid1a within tumors decreased chromatin accessibility and reduced transcription of genes associated with migration, invasion, and metastasis. In summary, ARID1A has context-dependent tumor-suppressive and oncogenic roles in cancer.
Genes encoding subunits of SWI/SNF (BAF) chromatin-remodeling complexes are collectively mutated in ∼20% of all human cancers. Although ARID1A is the most frequent target of mutations, the mechanism by which its inactivation promotes tumorigenesis is unclear. He
re we demonstrate that Arid1a functions as a tumor suppressor in the mouse colon, but not the small intestine, and that invasive ARID1A-deficient adenocarcinomas resemble human colorectal cancer (CRC). These tumors lack deregulation of APC/β-catenin signaling components, which are crucial gatekeepers in common forms of intestinal cancer. We find that ARID1A normally targets SWI/SNF complexes to enhancers, where they function in coordination with transcription factors to facilitate gene activation. ARID1B preserves SWI/SNF function in ARID1A-deficient cells, but defects in SWI/SNF targeting and control of enhancer activity cause extensive dysregulation of gene expression. These findings represent an advance in colon cancer modeling and implicate enhancer-mediated gene regulation as a principal tumor-suppressor function of ARID1A.
Kim YB, etal., Hum Pathol. 2016 Mar;49:61-70. doi: 10.1016/j.humpath.2015.10.008. Epub 2015 Nov 2.
AT-rich interactive domain 1A (ARID1A) is frequently mutated in gastric cancers, and loss of ARID1A expression is considered a poor prognostic factor in various cancers. However, in practice, ARID1A
ARID1A shows various expression patterns, and our understanding of its significance is limited. We performed immunohistochemistry for ARID1A, MLH1, and pS6 using whole tissue blocks of 350 gastric cancers and classified the ARID1A expression as follows: retained (63.7%), reduced (17.7%), complete loss (14.9%), and partial loss (3.7%). Complete/partial loss was more common in poorly differentiated histology (P < .001), and reduced or complete loss of ARID1A was frequent in cases with MLH1 loss (P < .001). The ARID1A-reduced group showed only slightly inferior disease-free survival (DFS; P = .254) and overall survival (OS; P = .377) compared to those of the ARID1A-retained group, whereas the group with complete loss showed significantly worse DFS (hazard ratio [HR], 1.732; P = .015) and OS (HR, 1.751; P = .013). Worse DFS (HR, 2.672; P = .005) and OS (HR, 2.531; P = .002) were also noted in the group with partial loss. High expression of pS6 was observed more frequently in groups showing altered ARID1A expression patterns (P < .001). In conclusion, reduced ARID1A expression is not a major prognostic determinant, although it may lead to AKT pathway activation. Tumor cells lacking ARID1A expression may influence the prognosis even if they constitute only a small proportion of the tumor sample. Our data provide an enhanced roadmap for understanding ARID1A with implications for future research and therapeutics.
Wei XL, etal., World J Gastroenterol. 2014 Dec 28;20(48):18404-12. doi: 10.3748/wjg.v20.i48.18404.
AIM: To explore the association between AT-rich interactive domain 1A (ARID1A) protein loss by immunohistochemistry and both clinicopathologic characteristics and prognosis in patients with colorectal cancer. METHODS: We retrospectively coll
ected clinicopathologic data and archived paraffin-embedded primary colorectal cancer samples from 209 patients, including 111 patients with colon cancer and 98 patients with rectal cancer. The tumor stage ranged from stage I to stage IV according to the 7(th) edition of the American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system. All patients underwent resection of primary colorectal tumors. The expression of ARID1A protein in primary colorectal cancer tissues was examined by immunohistochemical staining. The clinicopathologic association and survival relevance of ARID1A protein loss in colorectal cancer were analyzed. RESULTS: ARID1A loss by immunohistochemistry was not rare in primary colorectal cancer tumors (25.8%). There were 7.4%, 24.1%, 22.2% and 46.3% of patients with ARID1A loss staged at TNM stage I, II, III and IV, respectively, compared with 20.0%, 22.6%, 27.7% and 29.7% of patients without ARID1A loss staged at TNM stage I, II, III and IV, respectively. In patients with ARID1A loss, the distant metastasis rate was 46.3%. However, only 29.7% of patients without ARID1A loss were found to have distant metastasis. In terms of pathologic differentiation, there were 25.9%, 66.7% and 7.4% with poorly, moderately and well differentiated tumors in patients with ARID1A loss, and 14.2%, 72.3% and 13.5% with poorly, moderately and well differentiated tumors in patients without ARID1A loss, respectively. ARID1A loss was associated with late TNM stage (P = 0.020), distant metastasis (P = 0.026), and poor pathological classification (P = 0.035). However, patients with positive ARID1A had worse overall survival compared to those with negative ARID1A in stage IV colorectal cancer (HR = 2.49, 95%CI: 1.13-5.51). CONCLUSION: ARID1A protein loss is associated with clinicopathologic characteristics in colorectal cancer patients and with survival in stage IV patients.
Jiang ZH, etal., Eur Rev Med Pharmacol Sci. 2015 Sep;19(17):3194-200.
OBJECTIVE: The gene product of the AT-rich interactive domain 1A (SWI-like) gene (ARID1A) is a member of the SWI/SNF adenosine triphosphate-dependent chromatin-remodeling complexes, which plays an essential role in controlling gene expression and is also involv
ed in cancer development. ARID1A is frequently mutated in a wild variety of cancers and function as a tumor suppressor in several kinds of cancers. ARID1A was down-regulated in gastric cancer, and associated poor patient prognosis. However, how ARID1A protein is regulated in gastric cancer remains largely unknown. MATERIALS AND METHODS: Here, we show that ARID1A protein is rapidly ubiquitinated and degradated in gastric cancer cells in response to DNA damage treatment. RESULTS: Using genetic and pharmacologic Cullin inactivation coupled with in vitro ubiquitination assay, we demonstrate that ARID1A is a substrate of the Cullin-SKP1-F-box protein (SCF) complexes. Moreover, gastric cancer cells with forced expression of ARID1A showed an increased sensitivity to DNA damage reagents. Thus, our data uncovered a previous unknown posttranscriptional regulation of ARID1A by SCF E3 ligase in gastric cancer cells in DNA damage response. CONCLUSIONS: These findings suggest ARID1A might be a promising drug target in gastric cancer treatment.
Yang Y, etal., Anticancer Drugs. 2020 Apr;31(4):368-376. doi: 10.1097/CAD.0000000000000881.
Gastric cancer (GC) is lethal and there is an urgent need for improved understanding of this disease. Recent studies have reported that microRNAs (miRNAs) play increasingly important roles in the regulation of GC. In this study, we explored the target genes and effects of miR-7641 in GC. Our data sh
owed that high miR-7641 expression was associated with low expression of ARID1A in GC tissue. miR-7641 expression promoted GC cell proliferation and colony formation. Luciferase reporter assay results confirmed that ARID1A was a target gene of miR-7641. Furthermore, downregulation of ARID1A expression caused a significant increase in GC cell proliferation. In vivo depletion of miR-7641 reduced tumor volume and weight and increased ARID1A and Ki67 expression as well as a decreased terminal-deoxynucleotidyl transferase-mediated nick end labeling in mouse tumor tissues. Conversely, ARID1A silencing reversed the suppressive effects of miR-7641 inhibitors on GC cells. Overall, these findings indicate that miR-7641 is a promising novel prognostic biomarker of GC and may represent a novel target for clinical management of GC.
Hu C, etal., J Hepatol. 2018 Mar;68(3):465-475. doi: 10.1016/j.jhep.2017.10.028. Epub 2017 Nov 4.
BACKGROUND & AIMS: AT-rich interaction domain 1a (Arid1a), a component of the chromatin remodeling complex, has emerged as a tumor suppressor gene. It is frequently mutated in hepatocellular carcinoma (HCC). However, it remains unknown how Arid1a
='font-weight:700;'>Arid1a suppresses HCC development and whether Arid1a deficiency could be exploited for therapy, we aimed to explore these questions. METHODS: The expression of Arid1a in human and mouse HCCs was determined by immunohistochemical (IHC) staining. Gene expression was determined by quantitative PCR, ELISA or western blotting. Arid1a knockdown HCC cell lines were established by lentiviral-based shRNA. Tumor angiogenesis was quantified based on vessel density. The regulation of angiopoietin (Ang2) expression by Arid1a was identified by chromatin immunoprecipitation (ChIP) assay. The tumor promoting function of Arid1a loss was studied with a xenograft model in nude mice and diethylnitrosamine (DEN)-induced HCC in Arid1a conditional knockout mice. The therapeutic values of Ang2 antibody and sorafenib treatment were evaluated both in vitro and in vivo. RESULTS: We demonstrate that Arid1a deficiency, occurring in advanced human HCCs, is associated with increased vessel density. Mechanistically, loss of Arid1a causes aberrant histone H3K27ac deposition at the angiopoietin-2 (Ang2) enhancer and promoter, which eventually leads to ectopic expression of Ang2 and promotes HCC development. Ang2 blockade in Arid1a-deficient HCCs significantly reduces vessel density and tumor progression. Importantly, sorafenib treatment, which suppresses H3K27 acetylation and Ang2 expression, profoundly halts the progression of Arid1a-deficient HCCs. CONCLUSIONS: Arid1a-deficiency activates Ang2-dependent angiogenesis and promotes HCC progression. Loss of Arid1a in HCCs confers sensitivity to Ang2 blockade and sorafenib treatment. LAY SUMMARY: AT-rich interaction domain 1a (Arid1a), is a tumor suppressor gene. Arid1a-deficiency promotes Ang2-dependent angiogenesis leading to hepatocellular carcinoma progression. Arid1a-deficiency also sensitizes tumors to Ang2 blockade by sorafenib treatment.
Jang SH, etal., Pathol Res Pract. 2020 Nov;216(11):153156. doi: 10.1016/j.prp.2020.153156. Epub 2020 Aug 8.
Adenine-thymine-rich inactive domain-containing protein 1A (ARID1A) is a large subunit of the switch-sucrose nonfermenting (SWI-SNF) complex. ARID1A is considered to be a tumor suppressor in various cancers. We investigated
the clinicopathological significance including prognosis of ARID1A expression in non-small cell lung cancer (NSCLC). ARID1A expression was studied by tissue microarray immunohistochemical analysis of 171 surgically resected NSCLC specimens including adenocarcinoma (ADC) and squamous cell carcinoma (SCC) on tissue microarray. Semiquantitative immunohistochemical score was obtained by multiplying the intensity and percentage scores. The overall score was further simplified by dichotomizing into either negative (score < 4) or positive (score >= 4) for each patient. The ARID1A-negative group revealed significantly higher correlations with male sex (p = 0.020), larger tumor size (p = 0.007), SCC than with ADC (p = 0.023) and smoking (p = 0.001). Univariate survival analysis showed that the ARID1A-negative group had a significantly shorter cancer specific survival than the ARID1A-positive group (p = 0.018). Multivariate survival analysis showed that ARID1A negativity (p = 0.022) were independent prognostic factors related with shorter cancer specific survival for NSCLC. In conclusion, Loss of ARID1A expression is a potential molecular marker to predictive of poor prognosis of NSCLC.
Kim MJ, etal., Histopathology. 2015 Mar;66(4):508-16. doi: 10.1111/his.12566. Epub 2015 Jan 12.
AIMS: To investigate AT-rich interactive domain-containing protein 1A (ARID1A) and p53 expression in small intestinal carcinoma (SIC) and to determine its prognostic significance. METHODS AND RESULTS: Immunohistochemical staining for ARID1A
tyle='font-weight:700;'>ARID1A and p53 was performed in 178 SICs using a tissue microarray (TMA). Loss of or low ARID1A expression was observed in 36 (20.2%) and 60 (33.7%) of cases, respectively. Aberrant p53 expression was observed in 99 (55.6%) cases. Loss of or low ARID1A expression was found to be associated with signet ring cell carcinoma and undifferentiated carcinoma, a high-grade tumour, and a higher T stage. No relationship was found between aberrant p53 expression and clinicopathological factors or overall survival. Patients with loss of ARID1A expression, irrespective of p53 expressional status, showed significantly poorer overall survival than those expressing ARID1A. Multiple regression analysis revealed that grade and pT stage were associated significantly with ARID1A loss, and multivariate analysis showed that patients with high ARID1A expression had a lower risk of death than those with loss of ARID1A expression. CONCLUSIONS: Low or loss of ARID1A expression is correlated significantly with a high-grade tumour, higher T stage, and poorer overall survival. These findings suggest that ARID1A expression could be used as a prognostic marker in SIC.
Yang SZ, etal., World J Gastroenterol. 2016 Jul 7;22(25):5814-21. doi: 10.3748/wjg.v22.i25.5814.
AIM: To investigate the relationship between ARID1A expression and clinicopathologic parameters, as well as its prognostic value, for patients with intrahepatic cholangiocarcinoma (IHCC). METHODS: We assessed ARID1A
RID1A protein and mRNA expression in IHCC tissues and paracarcinomatous (PC) tissues from 57 patients with IHCC using western blot and quantitative real-time reverse transcription polymerase chain reaction, respectively. We used Fisher's exact and χ(2) tests to analyze relationships between clinicopathological parameters and ARID1A expression. The Kaplan-Meier method and Cox regression were used to analyze survival. RESULTS: The mean ARID1A protein level in IHCC tissues was 1.16 ± 0.36 relative units (RU), which was significantly lower than that in PC tissues (1.26 ± 0.21 RU, P < 0.01) and NL tissues (1.11 ± 0.31, P < 0.001). The mean ARID1A mRNA level in IHCC tissues (1.20 ± 0.18) was also lower than that in PC tissues (1.27 ± 0.15, P < 0.001) and normal liver tissues (1.15 ± 0.34, P < 0.001). Low ARID1A expression was significantly associated with tumor nodules, vein invasion, and recurrence. Median overall survival (OS) and disease-free survival (DFS) for the low ARID1A expression group was 15.0 and 7.0 mo, respectively, which were significantly shorter than those for the high ARID1A expression group at 25.0 and 22.0 mo (OS: P < 0.01; DFS: P < 0.001), respectively. Low ARID1A expression was significantly associated with worse OS (HR = 3.967, 95%CI: 1.299-12.118, P = 0.016) in multivariate analyses. CONCLUSION: Low expression of ARID1A is associated with poor prognosis in patients with IHCC, and thus may be a potential prognostic biomarker candidate in IHCC.
Wang X, etal., Biol Reprod. 2016 Apr;94(4):93. doi: 10.1095/biolreprod.115.133637. Epub 2016 Mar 9.
Women with endometriosis can suffer from decreased fecundity or complete infertility via abnormal oocyte function or impaired placental-uterine interactions required for normal pregnancy establishment and maintenance. Although AT-rich interactive domain 1A (SWI-like) (ARID1A
ARID1A) is a putative tumor suppressor in human endometrial cancers and endometriosis-associated ovarian cancers, little is known about its role in normal uterine function. To study the potential function of ARID1A in the female reproductive tract, we generated mice with a conditional knockout of Arid1a using anti-Mullerian hormone receptor 2-Cre Female Arid1a conditional knockout mice exhibited a progressive decrease in number of pups per litter, with a precipitous decline after the second litter. We observed no tumors in virgin mice, although one knockout mouse developed a uterine tumor after pregnancy. Unstimulated virgin female knockout mice showed normal oviductal, ovarian, and uterine histology. Uteri of Arid1a knockout mice showed a normal decidualization response and appropriate responses to estradiol and progesterone stimulation. In vitro studies using primary cultures of human endometrial stromal fibroblasts revealed that small interfering RNA knockdown of ARID1A did not affect decidualization in vitro. Timed pregnancy studies revealed the significant resorption of embryos at Embryonic Day 16.5 in knockout mice in the third pregnancy. In addition to evidence of implantation site hemorrhage, pregnant Arid1a knockout mice showed abnormal placental morphology. These results suggest that Arid1a supports successful pregnancy through its role in placental function.
Deletion of the frequently mutated AT-rich interacting domain-containing protein 1A (ARID1A), an SWI/SNF subunit, is associated with poor prognosis in various tumors. This study observed and analyzed ARID1A expression and it
s correlation with prognosis in gastric carcinoma. Postoperative sections of 98 patients with primary gastric cancer and 40 patients with gastric benign lesions were examined by immunohistochemistry. ARID1A deficiency was observed in 19.39% of gastric cancer tissues, 4.08% of matched paracancerous tissues, and 2.5% of normal gastric mucosa tissues. ARID1A expression was significantly down-regulated in gastric cancer tissues compared with paracancerous tissues (P = .001) and normal gastric mucosa tissues (P = .011). ARID1A deletion significantly correlated with tumor size (P = .022), lymph node metastasis (P = .030), and tumor differentiation (P = .009). In the 90 gastric cancer tissues with tumor stages II and III, the clinical outcome of the ARID1A-negative patients was significantly poorer than that of the ARID1A-positive patients (P = .005). Univariate analysis revealed that tumor invasion depth (P = .025), stage (P = .032), poor differentiation (P = .046), lymph node metastasis (P = .038), and ARID1A expression (P = .023) were significantly related to the overall survival of gastric cancer patients. Multivariate analysis demonstrated that tumor invasion depth (P = .029) and ARID1A expression (P = .031) were independent factors that indicate poor prognosis. In conclusion, the loss of ARID1A expression in gastric cancer patients significantly correlated with poor survival.
Shen J, etal., Cancer Discov. 2015 Jul;5(7):752-67. doi: 10.1158/2159-8290.CD-14-0849. Epub 2015 Jun 11.
ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A
style='font-weight:700;'>ARID1A deficiency can be exploited therapeutically. In this article, we report a key function of ARID1A in regulating the DNA damage checkpoint. ARID1A is recruited to DNA double-strand breaks (DSB) via its interaction with the upstream DNA damage checkpoint kinase ATR. At the molecular level, ARID1A facilitates efficient processing of DSB to single-strand ends and sustains DNA damage signaling. Importantly, ARID1A deficiency sensitizes cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with ARID1A-mutant tumors. SIGNIFICANCE: ARID1A has been identified as one of the most frequently mutated genes across human cancers. Our data suggest that clinical utility of PARP inhibitors might be extended beyond patients with BRCA mutations to a larger group of patients with ARID1A-mutant tumors, which may exhibit therapeutic vulnerability to PARP inhibitors.
Kim YB, etal., Int J Cancer. 2019 Aug 15;145(4):916-926. doi: 10.1002/ijc.32140. Epub 2019 Feb 8.
Notwithstanding remarkable treatment success with anti-PD-1 monoclonal antibody, oncogenic mechanism of PD-L1 regulation in gastric cancer (GC) remains poorly understood. We hypothesized that ARID1A might be related to tumor PD-L1 expression in GC. We found that
tumor PD-L1 positivity was associated with loss of ARID1A and showed trend toward better survival of patients with various molecular subtypes of GC (experimental set, n = 273). Considering heterogeneous ARID1A expression, we validated this using whole tissue sections (n = 159) and found that loss of ARID1A was correlated with microsatellite instability-high (MSI-H), Epstein-Barr virus (EBV), and PD-L1 positivity. Furthermore, for patients with MSI-H tumors, the degree of PD-L1 expression was significantly higher in ARID1A-deficient tumors. After ARID1A knockdown in GC cell lines, total and membranous PD-L1 protein, and PD-L1 mRNA levels were increased based on Western blot, flow cytometry, and qRT-PCR, respectively. With IFN-γ treatment, PD-L1 expression was significantly increased both in ARID1A-deficient cancer cells and controls, but the increase was not more pronounced in the former. Loss of ARID1A increased PD-L1 via activating AKT signaling, while LY294002 (PI3K inhibitor) decreased PD-L1 levels. Furthermore, we found that 3 MSI-H tumors showing highest expression of PD-L1 had simultaneous KRAS mutation and loss of ARID1A, suggesting a possible synergistic role boosting PD-L1. Our results strongly indicate that loss of ARID1A is tightly associated with high PD-L1 expression in GC. These results would increase our understanding of the oncogenic mechanism of PD-L1 regulation in GC, and also help to find the optimal candidates for immunotherapy.
Hepatocellular carcinoma (HCC) is one of the most common and lethal human cancers. Recently, exome sequencing has revealed that mutation of ARID1A is frequent in HCC. Herein, we determined the clinicopathologic significance of ARID1A
1A expression in HCC. We detected the level of mRNA and protein expression of ARID1A in 12 paired HCC tumors and adjacent non-cancerous tissues by quantitative real-time PCR and immunohistochemistry (IHC). In addition, we determined the expression of BAF250a on 121 HCC tumors by IHC and assessed the association between BAF250a expression and clinicopathologic and prognostic features. The levels of ARID1A mRNA were significantly elevated in 10 of 12 HCC tumors compared with adjacent non-cancerous tissues. The level of BAF250a protein expression was higher in 10 of 12 HCC tumors compared with adjacent liver tissues. IHC indicated that 12.17 % of HCC tumors (14/115) were BAF250a-negative. Loss of BAF250a was significantly associated with larger tumor size, but not associated with other clinicopathologic features. There was no significant difference in disease-free or overall survival between BAF250a-positive and BAF250a-negative patients. Most HCCs had an increased level of ARID1A mRNA and BAF250a expression. Loss of BAF250a was significantly more frequent in larger HCC tumors, but had no prognostic significance.
ARID1A, encoding a subunit of chromatin remodeling SWI/SNF complexes, has recently been considered as a new type of tumor suppressor gene for its somatic mutations frequently found in various human tumors, including hepatocellular carcinoma (HCC). However, the r
ole and mechanism of inactivated ARID1A mutations in tumorigenesis remain unclear. To investigate the role of ARID1A inactivation in HCC pathogenesis, we generated hepatocyte-specific Arid1a knockout (Arid1aLKO) mice by crossing mice carrying loxP-flanked Arid1a exon 8 alleles (Arid1af/f) with albumin promoter-Cre transgenic mice. Significantly, the hepatocyte-specific Arid1a deficiency results in mouse steatohepatitis and HCC development. In Arid1aLKO mice, we found that innate immune cells, including F4/80+ macrophages and CD11c+ neutrophil cells, infiltrate into the liver parenchyma, accompanied by the increased tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and activation of STAT3 and NF-kappaB pathways. In conclusion, hepatocyte-specific Arid1a deficiency could lead to mouse steatohepatitis and HCC development. This study provides an alternative mechanism by which Arid1a deficiency contributes to HCC tumorigenesis.
Yang Y, etal., Cancer Manag Res. 2019 May 29;11:4931-4946. doi: 10.2147/CMAR.S207329. eCollection 2019.
Background: AT-rich interactive domain-containing protein 1A (ARID1A) is a member of the switch/sucrose nonfermentable chromatin remodeling complex, which has been observed to be mutated in various tumors. The loss of ARID1A
is reported to be frequently associated with PI3K/Akt pathway activation. Objective: The roles of ARID1A in nasopharyngeal carcinoma (NPC) have not been reported until now. The aim of this research was to explore the clinical significance and potential mechanism of ARID1A in NPC development and progression. Methods: ARID1A expression levels were investigated in human NPC tissues and cell lines. The effects of ARID1A knockdown on nasopharyngeal cancer cell proliferation, migration and invasion were evaluated in vitro using CCK8, wound healing, transwell and flow cytometry assays. The expression of relevant proteins was evaluated by Western blot assays. Results: In this study, ARID1A was significantly downregulated in NPC tissues and cells. Furthermore, low ARID1A expression was significantly associated with aggressive clinicopathological characteristics and poor survival in NPC patients. Depletion of endogenous ARID1A by siRNA promoted proliferation, migration and invasion in CNE1 and HNE1 cells. Additionally, ARID1A knockdown increased the phosphorylation of Akt in NPC cells. High levels of p-Akt were also observed in NPC biopsies and correlated with ARID1A downregulation. These results imply that the loss of ARID1A could activate Akt signaling. In addition, MK-2206 (a highly selective inhibitor of Akt) partially suppressed NPC cell proliferation, migration and invasion, which were induced by ARID1A knockdown. Conclusion: Our findings indicate that ARID1A plays an essential role in modulating the Akt pathway, functions as a tumor suppressor in NPC and may be a potential target for NPC treatment.
Zhang X, etal., Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2017 Jan;33(1):77-80.
Objective To investigate the expression pattern and clinical significance of chromatin remodeling AT-rich interactive domain 1A (ARID1A) protein in gastric cancer and paired adjacent noncancerous tissue samples. Methods The expression of ARID1A
:700;'>ARID1A protein was examined in 90 gastric cancer tissue samples and 90 paired adjacent noncancerous tissue samples by immunohistochemistry. The relationship of ARID1A protein expression with clinical-pathological characteristics was evaluated by Mann-Whitney test and Spearman correlation analysis. The relationship with clinical prognosis was analyzed by Kaplan-Meier survival curve, Log-Rank test and Cox regression model. Results ARID1A was expressed in both cytoplasm and nucleus of adjacent noncancerous tissues and gastric cancer tissues. Both cytoplasmic and nuclear ARID1A expressions significantly decreased in gastric cancer tissues compared with adjacent noncancerous tissues. Cytoplasmic ARID1A expression in adjacent noncancerous tissues was negatively correlated with clinical TNM stage. Meanwhile, nuclear ARID1A expression in adjacent noncancerous tissues was positively correlated with patients' age and negatively correlated with tumor size. Survival analysis showed that cytoplasmic ARID1A expression in adjacent noncancerous tissues was related with overall survival but not significantly, and that both cytoplasmic and nuclear ARID1A expressions in gastric cancer tissues were not related with clinical-pathological characteristics and prognosis. Conclusion ARID1A may play an important role in the early events of gastric carcinogenesis, and it can serve as a potential biomarker for early diagnosis.
Han X, etal., Pancreas. 2020 Apr;49(4):514-523. doi: 10.1097/MPA.0000000000001535.
OBJECTIVE: The genetic aberrations that underlie chromatin remodeling in sporadic nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) remain largely unknown. Here, we investigated the dysregulation of the switch/sucrose nonfermentable (SWI/SNF) component ARID1A
;'>ARID1A and its correlation with clinicopathological features and prognosis. METHODS: We sequenced the exomes of sporadic NF-pNETs. Quantitative real-time polymerase chain reaction and immunohistochemistry were used to determine messenger RNA level and protein expression. RESULTS: The sporadic NF-pNETs harbored 264 somatic mutations in 228 different genes, most commonly affecting the SWI/SNF components ARID1B (57.1%) and ARID1A (42.9%). The expression of ARID1A was remarkably downregulated in NF-pNETs and corresponding liver metastases compared with that in normal pancreatic islet tissue. Reduced expression of ARID1A was associated with malignant clinicopathological features (P < 0.05). The loss of ARID1A was related to a high Ki-67 index (P < 0.05). Patients with ARID1A-negative expression had a significantly worse overall survival rate than those with ARID1A-positive expression (P < 0.05). The ARID1A status was an independent predictor of overall survival, and a nomogram integrating ARID1A with clinicopathological features was proposed. CONCLUSIONS: The loss of SWI/SNF components ARID1A may be associated with malignant behaviors and an unfavorable prognosis. Aberrations of ARID1A may contribute to tumorigenesis and metastasis in sporadic NF-pNETs.
Lee LH, etal., Hum Pathol. 2016 Jul;53:97-104. doi: 10.1016/j.humpath.2016.02.004. Epub 2016 Mar 2.
ARID1A is a chromatin remodeling gene that is mutated in a number of cancers including colorectal carcinoma (CRC). Loss of ARID1A has been associated with an adverse outcome in some types of cancer. However, literature data
have not been consistent. Major limitations of some outcome studies include small sample size and heterogeneous patient population. In this study, we evaluated the prognostic value of ARID1A in a homogeneous group of early stage CRC patients, a population where prognostic markers are particularly relevant. We collected a retrospective series of 578 stage I or II CRCs. All patients underwent surgery with curative intent and without neoadjuvant or adjuvant therapy. ARID1A expression was analyzed by immunohistochemistry using tissue microarray. We found ARID1A loss in 49 of 552 analyzable tumors (8.9%). Compared with the ARID1A-retained group, cases with ARID1A loss were associated with female sex (P<.001), mismatch-repair protein deficiency (P<.001), poor differentiation (P<.001), lymphovascular invasion (P=.001), and higher pT stage (P=.047). However, at a median follow-up of 49months, ARID1A loss did not correlate with overall, disease-specific, or recurrence-free survival. This is the first systematic analysis to evaluate the prognostic significance of ARID1A in stage I/II CRCs, and our data indicate that ARID1A loss lacks prognostic significance in this population despite its association with other adverse features. Such data are clinically relevant, as efforts are ongoing in identifying markers that can detect the small but significant subset of early stage CRCs that will have a poor outcome.
Inada R, etal., World J Gastroenterol. 2015 Feb 21;21(7):2159-68. doi: 10.3748/wjg.v21.i7.2159.
AIM: To analyze the mismatch repair (MMR) status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas. METHODS: We examined the expressions of MMR proteins and ARID1A
ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas. The results were further correlated with clinicopathological variables. RESULTS: The loss of any MMR protein expression, indicative of MMR deficiency, was observed in 38 cases (7.8%) and was significantly associated with an older age (68.6±9.2 vs 60.4±11.7, P<0.001), a female sex (55.3% vs 31.3%, P=0.004), an antral location (44.7% vs 25.7%, P=0.021), and a differentiated histology (57.9% vs 39.7%, P=0.023). Abnormal ARID1A expression, including reduced or loss of ARID1A expression, was observed in 109 cases (22.3%) and was significantly correlated with lymphatic invasion (80.7% vs 69.5%, P=0.022) and lymph node metastasis (83.5% vs 73.7%, P=0.042). The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency (47.4% vs 20.2%, P<0.001). A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor (HR=1.36, 95%CI: 1.01-1.84; P=0.040). CONCLUSION: Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion, lymph node metastasis, poor prognosis, and MMR deficiency in gastric adenocarcinomas.
The AT-rich interactive domain 1A gene (ARID1A), which encodes one of the subunits in the Switch/Sucrose Nonfermentable chromatin remodeling complex, carries mutations and is responsible for loss of protein expression in gastric carcinoma, particularly with Epst
ein-Barr virus (EBV) infection and a microsatellite instability-high phenotype. We used immunohistochemistry to investigate the significance of ARID1A loss in 857 gastric carcinoma cases, including 67 EBV(+) and 136 MLH1-lost gastric carcinomas (corresponding to a microsatellite instability-high phenotype). Loss of ARID1A expression was significantly more frequent in EBV(+) (23/67; 34 %) and MLH1-lost (40/136; 29 %) gastric carcinomas than in EBV(-)MLH1-preserved (32/657; 5 %) gastric carcinomas (P < 0.01). Loss of ARID1A correlated with larger tumor size, advanced invasion depth, lymph node metastasis, and poor prognosis in EBV(-)MLH1-preserved gastric carcinoma. A correlation was found only with tumor size and diffuse-type histology in MLH1-lost gastric carcinoma, but no correlation was observed in EBV(+) gastric carcinoma. Loss of ARID1A expression in EBV(+) gastric carcinoma was highly frequent in the early stage of gastric carcinoma, although EBV infection did not cause downregulation of ARID1A: EBV-positive nasopharyngeal carcinomas (n = 8) and lymphomas (n = 15) failed to show loss of ARID1A, and EBV infection did not cause loss of ARID1A in gastric carcinoma cell lines. Taken together, loss of ARID1A may be an early change in carcinogenesis and may precede EBV infection in gastric epithelial cells, while loss of ARID1A promotes cancer progression in gastric cancer cells without EBV infection or loss of MLH1 expression. Loss of ARID1A has different and pathway-dependent roles in gastric carcinoma.
Inactivation of the ARID1A tumour suppressor gene is frequent in ovarian endometrioid (OEC) and clear cell (OCCC) carcinomas, often in conjunction with mutations activating the PI3K-AKT and/or canonical Wnt signalling pathways. Prior work has shown that conditio
nal bi-allelic inactivation of the Apc and Pten tumour suppressor genes in the mouse ovarian surface epithelium (OSE) promotes outgrowth of tumours that reflect the biological behaviour and gene expression profiles of human OECs harbouring comparable Wnt and PI3K-AKT pathway defects, although the mouse tumours are more poorly differentiated than their human tumour counterparts. We found that conditional inactivation of one or both Arid1a alleles in OSE concurrently with Apc and Pten inactivation unexpectedly prolonged the survival of tumour-bearing mice and promoted striking epithelial differentiation of the cancer cells, resulting in morphological features akin to those in human OECs. Enhanced epithelial differentiation was linked to reduced expression of the mesenchymal markers N-cadherin and vimentin, and increased expression of the epithelial markers Crb3 and E-cadherin. Global gene expression profiling showed enrichment for genes associated with mesenchymal-epithelial transition in the Arid1a-deficient tumours. We also found that an activating (E545K) Pik3ca mutation, unlike Pten inactivation or Pik3ca H1047R mutation, cannot cooperate with Arid1a loss to promote ovarian cancer development in the mouse. Our results indicate that the Arid1a tumour suppressor gene has a key role in regulating OEC differentiation, and paradoxically the mouse cancers with more initiating tumour suppressor gene defects had a less aggressive phenotype than cancers arising from fewer gene alterations. Microarray data have been deposited in NCBI's Gene Expression Omnibus (GSE67695).
Zhang Y, etal., Tumour Biol. 2014 Jun;35(6):5701-7. doi: 10.1007/s13277-014-1755-x. Epub 2014 Feb 26.
ARID1A (AT-rich interactive domain 1A) is a key member of the SWI/SNF chromatin-modeling complex, and the gene has emerged as a tumor suppressor in various human cancers. In the present study, we investigated the expression and clinical significance of ARID1A
le='font-weight:700;'>ARID1A in non-small cell lung cancer (NSCLC). We found that ARID1A expression was decreased in NSCLC tissues compared with normal bronchial epithelium and was significantly correlated with nodal metastasis, tumor, node, metastasis (TNM) stage, and poor differentiation. ARID1A expression was lower in lung cancer cell lines than normal bronchial epithelial HBE cell line. We also explored the involvement of ARID1A in biological behavior of lung cancer cell lines. ARID1A depletion by small interfering RNA (siRNA) in H460 and H1299 cell lines promoted proliferation, colony formation ability, and inhibited paclitaxel-induced apoptosis. Furthermore, we identified that ARID1A regulated several cell cycle and apoptosis-related targets such as cyclin D1 and Bcl-2. In addition, the activity of Akt phosphorylation was also enhanced after ARID1A depletion. In conclusion, our data suggested that ARID1A may serve as an important tumor suppressor in NSCLC.
Allo G, etal., Mod Pathol. 2014 Feb;27(2):255-61. doi: 10.1038/modpathol.2013.144. Epub 2013 Jul 26.
BAF250a (ARID1A) loss is a frequent event in high-grade endometrial cancers. It has been proposed that ARID1A is a driver gene, with ARID1A mutations occurring secondary to deregulated m
ismatch repair mechanism in gastric cancers, representing an alternative oncogenic pathway to p53 alteration. The prognostic significance of ARID1A loss is controversial. In this study, we investigated the frequency of BAF250a immunohistochemical loss in a cohort of high-grade endometrial cancers (n=190) and correlated it with mismatch repair (hMLH1, hMSH2, hMSH6, and hPMS2) and p53 protein expression. The 190 cases consisted of 82 high-grade endometrioid, 88 serous, 10 clear cell, and 10 mixed (carcinosarcomas and mixed histology). There was BAF250a loss in 55/190 (29%) cancers, most commonly in high-grade endometrioid carcinomas (46 vs 9% in serous carcinomas, P<0.0001). Loss of any mismatch repair proteins was observed in 63/190 (33%) cancers, most commonly in high-grade endometrioid carcinomas (57 vs 10% in serous carcinomas, P<0.0001). Aberrant p53 expression was found in 86/190 (45%) cancers, more commonly in serous carcinomas (77 vs 18% in high-grade endometrioid carcinomas, P<0.0001). BAF250a loss was associated with mismatch repair loss (P<0.0001) and normal p53 expression (P<0.0001). These associations were maintained in the subset analysis within the high-grade endometrioid (P=0.026 and P=0.0083, respectively) and serous carcinoma cases (P=0.0031 and P<0.0001, respectively). Survival analysis revealed a superior progression-free survival (P=0.017) for patients with BAF250a loss within the entire cohort but not within the high-grade endometrioid and serous subtypes. Additionally, data from The Cancer Genome Atlas were extracted to correlate mutations in ARID1A, TP53, and MMR genes; we found that ARID1A mutations were negatively associated with TP53 mutations but were unrelated to mismatch repair gene mutations. In conclusion, BAF250a loss is more common in high-grade endometrioid carcinomas than in other high-grade endometrial cancers and is associated with mismatch repair deficiency and normal p53 expression.
Mehrvarz Sarshekeh A, etal., Clin Cancer Res. 2021 Mar 15;27(6):1663-1670. doi: 10.1158/1078-0432.CCR-20-2404. Epub 2021 Jan 7.
PURPOSE: AT-rich interactive domain 1A (ARID1A) is commonly mutated in colorectal cancer, frequently resulting in truncation and loss of protein expression. ARID1A recruits MSH2 for mismatch repair during DNA repl
ication. ARID1A deficiency promotes hypermutability and immune activation in preclinical models, but its role in patients with colorectal cancer is being explored. EXPERIMENTAL DESIGN: The DNA sequencing and gene expression profiling of patients with colorectal cancer were extracted from The Cancer Genome Atlas and MD Anderson Cancer Center databases, with validation utilizing external databases, and correlation between ARID1A and immunologic features. IHC for T-cell markers was performed on a separate cohort of patients. RESULTS: Twenty-eight of 417 patients with microsatellite stable (MSS) colorectal cancer (6.7%) had ARID1A mutation. Among 58 genes most commonly mutated in colorectal cancer, ARID1A mutation had the highest increase with frameshift mutation rates in MSS cases (8-fold, P < 0.001). In MSS, ARID1A mutation was enriched in immune subtype (CMS1) and had a strong correlation with IFNγ expression (Δz score +1.91, P < 0.001). Compared with ARID1A wild-type, statistically significant higher expression for key checkpoint genes (e.g., PD-L1, CTLA4, and PDCD1) and gene sets (e.g., antigen presentation, cytotoxic T-cell function, and immune checkpoints) was observed in mutant cases. This was validated by unsupervised differential expression of genes related to immune response and further confirmed by higher infiltration of T cells in IHC of tumors with ARID1A mutation (P = 0.01). CONCLUSIONS: The immunogenicity of ARID1A-mutant cases is likely due to an increased level of neoantigens resulting from increased tumor mutational burden and frameshift mutations. Tumors with ARID1A mutation may be more susceptible to immune therapy-based treatment strategies and should be recognized as a unique molecular subgroup in future immune therapy trials.
Guan B, etal., Cancer Res. 2011 Nov 1;71(21):6718-27. doi: 10.1158/0008-5472.CAN-11-1562. Epub 2011 Sep 7.
ARID1A (BAF250A) promotes the formation of SWI/SNF chromatin remodeling complexes containing BRG1 or BRM. It has emerged as a candidate tumor suppressor based on its frequent mutations in ovarian clear cell and endometrioid cancers and in uterine endometrioid ca
rcinomas. Here, we report that restoring wild-type ARID1A expression in ovarian cancer cells that harbor ARID1A mutations is sufficient to suppress cell proliferation and tumor growth in mice, whereas RNA interference-mediated silencing of ARID1A in nontransformed epithelial cells is sufficient to enhance cellular proliferation and tumorigenicity. Gene expression analysis identified several downstream targets of ARID1A including CDKN1A and SMAD3, which are well-known p53 target genes. In support of the likelihood that p53 mediates the effects of ARID1A on these genes, we showed that p53 was required and sufficient for their regulation by ARID1A. Furthermore, we showed that CDKN1A (encoding p21) acted in part to mediate growth suppression by ARID1A. Finally, we obtained evidence that the ARID1A/BRG1 complex interacted directly with p53 and that mutations in the ARID1A and TP53 genes were mutually exclusive in tumor specimens examined. Our results provide functional evidence in support of the hypothesis that ARID1A is a bona fide tumor suppressor that collaborates with p53 to regulate CDKN1A and SMAD3 transcription and tumor growth in gynecologic cancers.
Kishida Y, etal., Am J Clin Pathol. 2019 Sep 9;152(4):463-470. doi: 10.1093/ajcp/aqz062.
OBJECTIVES: To evaluate the relationships between adenine-thymine-rich interactive domain 1A (ARID1A) expression and the clinicopathologic features in T1 colorectal cancer (CRC) and to investigate whether the presence of ARID1A
>ARID1A protein is related to genetic changes. METHODS: We retrospectively studied 219 surgically resected T1 CRCs. ARID1A expression was assessed by immunohistochemical methods, and the correlation between ARID1A expression and clinicopathologic features was evaluated. The relationship between ARID1A expression and 409 cancer-related gene mutations was also evaluated using next-generation sequencing (NGS). RESULTS: Immunohistochemical staining indicated negative ARID1A expression in 4.6%. Loss of ARID1A expression was significantly associated with younger age, lymphatic invasion, and lymph node metastasis (LNM). NGS showed that PKHD1, RNF213, and MSH6 mutations were more frequent in ARID1A-negative tumors, whereas KRAS mutations were more common in ARID1A-positive tumors. CONCLUSIONS: In T1 CRC, negative ARID1A expression was correlated with early onset, lymphatic invasion, and LNM. Mutations in some cancer-related genes were possibly related with ARID1A expression.
He F, etal., J Exp Clin Cancer Res. 2015 May 15;34:47. doi: 10.1186/s13046-015-0164-3.
BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignancy worldwide, which is especially prevalent in Asia. Elucidating the molecular basis of HCC is crucial to develop targeted diagnostic tools and novel therapies. Recent studies have identified AT-rich interactive domain-contain
ing protein 1A (ARID1A) as a broad-spectrum tumor suppressor. We evaluated the clinical implications of decreased ARID1A expression in HCC, and investigated the mechanisms of ARID1A-mediated tumor suppression. METHODS: Quantitative PCR, western blotting, immunohistochemical analysis of ARID1A mRNA and protein expression was conducted in 64 paired HCC and adjacent non-tumorous tissues. ARID1A function was evaluated in vitro in MHCC-97H and Huh7 HCC cell lines, and in vivo in a xenografted HCC tumor model. RESULTS: ARID1A mRNA and protein expression were significantly decreased in HCC tissues, and decreased expression was significantly associated with overall metastasis, including local lymph node and distant metastasis, and poor prognosis. ARID1A knockdown promoted HCC cell migration and invasion in vitro, whereas overexpression of ARID1A inhibited migration and invasion. E-cadherin levels were closely correlated with ARID1A expression, suggesting a role in migration and invasion. In addition, ARID1A and E-cadherin (CDH1) expression were found to be regulated in a coordinated fashion in HCC samples. Furthermore, ARID1A knockdown significantly increased HCC tumor growth and lung metastasis in vivo. CONCLUSIONS: ARID1A served as an important tumor suppressor. Decreased expression of ARID1A was associated with tumor progression, metastasis, and reduced overall survival in mice and humans. ARID1A could represent a promising candidate therapeutic target for HCC.
BACKGROUND: The ARID1A gene encodes adenine-thymine (AT)-rich interactive domain-containing protein 1A, which participates in chromatin remodeling. ARID1A has been showed to function as a tumor suppressor in vario
us cancer types. In the current study, we investigated the expression and prognosis value of ARID1A in primary gastric cancer. Meanwhile, the biological role of ARID1A was further investigated using cell model in vitro. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the role of ARID1A gene in primary gastric cancer pathogenesis, real-time quantitative PCR and western blotting were used to examine the ARID1A expression in paired cancerous and noncancerous tissues. Results revealed decreased ARID1A mRNA (P = 0.0029) and protein (P = 0.0015) expression in most tumor-bearing tissues compared with the matched adjacent non-tumor tissues, and in gastric cancer cell lines. To further investigate the clinicopathological and prognostic roles of ARID1A expression, we performed immunohistochemical analyses of the 224 paraffin-embedded gastric cancer tissue blocks. Data revealed that the loss of ARID1A expression was significantly correlated with T stage (P = 0.001) and grade (P = 0.006). Consistent with these results, we found that loss of ARID1A expression was significantly correlated with poor survival in gastric cancer patients (P = 0.003). Cox regression analyses showed that ARID1A expression was an independent predictor of overall survival (P = 0.029). Furthermore, the functions of ARID1A in the proliferation and colony formation of gastric cell lines were analyzed by transfecting cells with full-length ARID1A expression vector or siRNA targeting ARID1A. Restoring ARID1A expression in gastric cancer cells significantly inhibited cell proliferation and colony formation. Silencing ARID1A expression in gastric epithelial cell line significantly enhanced cell growth rate. CONCLUSIONS/SIGNIFICANCE: Our data suggest that ARID1A may play an important role in gastric cancer and may serve as a valuable prognostic marker and potential target for gene therapy in the treatment of gastric cancer.
Ibarrola-Villava M, etal., Oncotarget. 2015 Sep 29;6(29):26935-45. doi: 10.18632/oncotarget.4775.
Genetic and epigenetic alterations play an important role in gastric cancer (GC) pathogenesis. Aberrations of the phosphatidylinositol-3-kinase signaling pathway are well described. However, emerging genes have been described such as, the chromatin remodeling gene ARID1A
ID1A. Our aim was to determine the expression levels of four GC-related genes, ARID1A, CDH1, cMET and PIK3CA, and 14 target-related microRNAs (miRNAs). We compared mRNA and miRNA expression levels among 66 gastric tumor and normal adjacent mucosa samples using quantitative real-time reverse transcription PCR. Moreover, ARID1A, cMET and PIK3CA protein levels were assessed by immunohistochemistry (IHC). Finally, gene and miRNAs associations with clinical characteristics and outcome were also evaluated. An increased cMET and PIK3CA mRNA expression was found in 78.0% (P = 2.20 x 10-5) and 73.8% (P = 1.00 x 10-3) of the tumors, respectively. Moreover, IHC revealed that cMET and PIK3CA expression was positive in 63.6% and 87.8% of the tumors, respectively. Six miRNAs had significantly different expression between paired-samples, finding five up-regulated [miR-223-3p (P = 1.65 x 10-6), miR-19a-3p (P = 1.23 x 10-4), miR-128-3p (P = 3.49 x 10-4), miR-130b-3p (P = 1.00 x 10-3) and miR-34a-5p (P = 4.00 x 10-3)] and one down-regulated [miR-124-3p (P = 0.03)]. Our data suggest that cMET, PIK3CA and target-related miRNAs play an important role in GC and may serve as potential targets for therapy.
González I, etal., Hum Pathol. 2019 Mar;85:18-26. doi: 10.1016/j.humpath.2018.10.013. Epub 2018 Oct 28.
Small intestinal adenocarcinoma is an uncommon neoplasm with poor prognosis. It is clinically approached similarly to colorectal carcinoma (CRC). The prognostic value of DNA mismatch repair protein deficiency (dMMR) in CRC is well established, but its role in small intestinal adenocarcinoma remains
inconclusive. Recently, loss of expression of ARID1A, a tumor suppressor gene product, by immunohistochemistry (IHC) was linked to dMMR and poor outcome in small intestinal adenocarcinoma, suggesting that it may be an emerging prognostic biomarker. We hypothesized that dMMR and/or ARID1A loss may be associated with clinical outcome in small intestinal adenocarcinoma. We examined dMMR and ARID1A loss by IHC in 120 surgically resected, nonampullary small intestinal adenocarcinomas collected from 2 tertiary centers. ARID1A loss was detected in 6 (7%) of 92 ARID1A-stained adenocarcinomas, whereas 21 (18%) of 120 adenocarcinomas demonstrated dMMR. ARID1A loss was not associated with survival or dMMR. dMMR adenocarcinomas had no distant metastasis, whereas 22 (22%) of 99 MMR-proficient adenocarcinomas had (P = .01). dMMR was an independent, positive predictor of disease-free survival (P = .035, hazard ratio: 0.2). Compared with dMMR CRC, dMMR small intestinal adenocarcinomas more frequently demonstrated loss of MSH2 and MSH6 and less often showed loss of MLH1 and PMS2 (both P < .001). In summary, ARID1A loss by IHC is uncommon in small intestinal adenocarcinomas. dMMR small intestinal adenocarcinomas are nonmetastatic tumors, frequently demonstrate loss of MSH2 and MSH6, and have superior disease-free survival. Our results suggest that all small intestinal adenocarcinomas should be tested for MMR protein deficiency.
Kosho T and Okamoto N, Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75. doi: 10.1002/ajmg.c.31407. Epub 2014 Aug 28.
Coffin-Siris syndrome (CSS) is a rare congenital malformation syndrome, recently found to be caused by mutations in several genes encoding components of the BAF complex. To date, 109 patients have been reported with their mutations: SMARCB1 (12%), SMARCA4 (11%), SMARCE1 (2%), ARID1A
ht:700;'>ARID1A (7%), ARID1B (65%), and PHF6 (2%). We review genotype-phenotype correlation of all previously reported patients with mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A through reassessment of their clinical and molecular findings. Cardinal features of CSS included variable degrees of intellectual disability (ID) predominantly affecting speech, sucking/feeding difficulty, and craniofacial (thick eyebrows, long eyelashes), digital (hypoplastic 5th fingers or toes, hypoplastic 5th fingernails or toenails), and other characteristics (hypertrichosis). In addition, patients with SMARCB1 mutations had severe neurodevelopmental deficits including severe ID, seizures, CNS structural abnormalities, and no expressive words as well as scoliosis. Especially, those with a recurrent mutation "p.Lys364del" represented strikingly similar phenotypes including characteristic facial coarseness. Patients with SMARCA4 mutations had less coarse craniofacial appearances and behavioral abnormalities. Patients with SMARCE1 mutations had a wide spectrum of manifestations from severe to moderate ID. Patients with ARID1A also had a wide spectrum of manifestations from severe ID and serous internal complications that could result in early death to mild ID. Mutations in SMARCB1, SMARCA4, and SMARCE1 are expected to exert dominant-negative or gain-of-function effects, whereas those in ARID1A are expected to exert loss-of-function effects.
Bi C, etal., BMC Cancer. 2019 Mar 8;19(1):213. doi: 10.1186/s12885-019-5429-3.
BACKGROUND: Although surgical resection provides a cure for patients with intrahepatic cholangiocarcinoma (ICC), the risk of mortality and recurrence remains high. Several biomarkers are reported to be associated with the prognosis of ICC, including Beclin-1, ARID1A
'>ARID1A, carbonic anhydrase IX (CA9) and isocitrate dehydrogenase 1 (IDH1), but results are inconsistent. Therefore, a histopathological retrospective study was performed to simultaneously investigate the relationship of these four potential biomarkers with clinicopathological parameters and their prognostic values in patients with ICC. METHODS: A total of 113 patients with ICC were enrolled from Cancer Hospital of Chinese Academy of Medical Sciences between January 1999 and June 2015. The expression of Beclin-1, ARID1A, IDH1 and CA9 were determined by immunohistochemical staining. The prognostic values of the four biomarkers were analyzed by Cox regression and the Kaplan-Meier method. RESULTS: Beclin-1, ARID1A, CA9 and IDH1 were highly expressed in ICC tumor tissues. Higher mortality was positively associated with Beclin-1 expression (HR = 2.39, 95% CI = 1.09-5.24) and higher recurrence was positively associated with ARID1A expression (HR = 1.71, 95% CI = 1.06-2.78). Neither CA9 nor IDH1 expression was significantly associated with mortality or disease recurrence. Kaplan-Meier survival curves showed that ICC patients with higher Beclin-1 and ARID1A expression had a lower survival rate and a worse recurrence rate than patients with low Beclin-1 and ARID1A expression (p < 0.05). CONCLUSIONS: High Beclin-1 and ARIDIA expression are strongly associated with poor prognosis in ICC patients, and thus Beclin-1 and ARID1A should be simultaneously considered as potential prognostic biomarkers for ICC patients.
Bateman NW, etal., Biochem Biophys Res Commun. 2016 Jan 1;469(1):114-9. doi: 10.1016/j.bbrc.2015.11.080. Epub 2015 Nov 22.
AT-rich interactive domain-containing protein 1A (ARID1A) is a recently identified nuclear tumor suppressor frequently altered in solid tumor malignancies. We have identified a bipartite-like nuclear localization sequence (NLS) that contributes to nuclear import
of ARID1A not previously described. We functionally confirm activity using GFP constructs fused with wild-type or mutant NLS sequences. We further show that cyto-nuclear localized, bipartite NLS mutant ARID1A exhibits greater stability than nuclear-localized, wild-type ARID1A. Identification of this undescribed functional NLS within ARID1A contributes vital insights to rationalize the impact of ARID1A missense mutations observed in patient tumors.
AT-rich interactive domain-containing protein 1A (ARID1A), a chromatin remodeling gene recently discovered to be a tumor suppressor in ovarian cancers, has been found to be mutated at low frequencies in many other tumors including colorectal carcinoma (CRC). An
association between ARID1A alteration and DNA mismatch repair (MMR) deficiency has been implicated; understanding this association may facilitate the understanding of the role of ARID1A in the various tumors. In this pilot study, we analyzed the immunohistochemical expression of ARID1A in a consecutive series of 257 CRCs that fulfilled a set of relaxed criteria for Lynch syndrome screening; 59 (23%) were MMR deficient by immunohistochemistry (44 MLH1/PMS2 deficient, 9 MSH2/MSH6 deficient, 4 MSH6 deficient, and 2 PMS2 deficient). ARID1A loss was observed in 9% (22/257) of the cohort: 24% of MMR-deficient tumors (14/59, 13 of the 14 being MLH1/PMS2 deficient) and 4% of MMR-normal tumors (8/198) (P < .05). MLH1 (mutL homolog 1) promoter hypermethylation was observed in 10 of the 13 MLH1/PMS2-deficient/ARID1A-loss tumors, indicating an association between ARID1A loss and sporadic microsatellite unstable CRCs. Among the MMR-deficient cases, ARID1A loss correlated with old age (P = .04), poor tumor differentiation (P < .01), medullary histology (P < .01), and an increased rate of nodal and distant metastasis (P = .03); these patients also trended toward a worse 5-year overall survival. Among MMR-normal tumors, no differences in clinicopathological features were detected between the groups stratified by ARID1A. In conclusion, our results suggest that ARID1A loss may be linked to a specific subset of sporadic microsatellite unstable CRCs that may be medullary but is more likely to present with metastatic disease, warranting further investigation.
Suryo Rahmanto Y, etal., J Biol Chem. 2016 Apr 29;291(18):9690-9. doi: 10.1074/jbc.M115.707612. Epub 2016 Mar 7.
ARID1A is a tumor suppressor gene that belongs to the switch/sucrose non-fermentable chromatin remodeling gene family. It is mutated in many types of human cancer with the highest frequency in endometrium-related ovarian and uterine neoplasms including ovarian
clear cell, ovarian endometrioid, and uterine endometrioid carcinomas. We have previously reported that mutations in the promoter of human telomerase reverse transcriptase (TERT) rarely co-occur with the loss of ARID1A protein expression, suggesting a potential role of ARID1A in telomere biology. In this study, we demonstrate that ARID1A negatively regulates TERT transcriptional regulation and activity via binding to the regulatory element of TERT and promotes a repressive histone mode. Induction of ARID1A expression was associated with increased occupancy of SIN3A and H3K9me3, known transcription repressor and histone repressor marks, respectively. Thus, loss of ARID1A protein expression caused by inactivating mutations reactivates TERT transcriptional activity and confers a survival advantage of tumor cells by maintaining their telomeres.
Sausen M, etal., Nat Genet. 2013 Jan;45(1):12-7. doi: 10.1038/ng.2493. Epub 2012 Dec 2.
Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma, we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases) and targeted analy
ses of specific genomic loci (40 cases) using massively parallel sequencing. On average, each tumor had 19 somatic alterations in coding genes (range of 3-70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of the chromatin-remodeling genes ARID1A and ARID1B were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight the dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of patients with neuroblastoma.
Recent whole-genome sequencing showed frequent mutations of ARID1A in gastric cancer (GC). In this study of a large independent Central European cohort, we evaluated the expression of ARID1A in whole tissue sections (WTS) of
GC testing the following hypotheses: ARID1A shows intratumoral heterogeneity, and ARID1A expression and/or heterogeneity correlates with clinicopathological patient characteristics. ARID1A expression was studied by immunohistochemistry in 450 primary GCs and 143 corresponding lymph node metastases. The expression pattern was correlated with clinicopathological characteristics and patient survival. ARID1A genotype and CpG methylation status were additionally analyzed in 7 GCs with a heterogeneous "black-and-white" expression pattern. ARID1A was expressed heterogeneously in 23 (5.1%) GCs, depicting a black-and-white pattern of negative and positive tumor areas. Complete loss of expression was found in 43 (9.6%) GCs. ARID1A status correlated significantly with tumor type according to Laurén, Epstein-Barr virus status, microsatellite instability, PD-L1 status, and nodal spread. There was no correlation with patient survival. In 4 cases with heterogeneous ARID1A expression, frame shift variants were detected. Summing up, heterogeneous or complete loss of ARID1A expression occurred in 14.7% of GCs and correlated with PD-L1 status, indicating potential for future combined anti-PD-L1/ARID1A therapy. In a subgroup of cases, ARID1A loss was heterogeneous, which suggests that ARID1A mutations might be a later event in gastric carcinogenesis.
Ye Y, etal., J BUON. 2018 Jul-Aug;23(4):1082-1091.
PURPOSE: Mutations in the gene encoding the AT-rich interacting domain containing protein 1A (ARID1A) are frequently observed in endometrial cancer, although the molecular mechanisms linking the genetic changes remain poorly understood. This study aim
ed to elucidate the influence of ARID1A mutations on endometrial cancer cells and tissues. METHODS: Reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blot and immunohistochemistry (IHC) were used to investigate the expression of ARID1A in endometrial cancer cells and tissues. Lentiviral vector (LV)-shARID1A was constructed and transfected into HEC-1-A cells. The efficiency of mutated ARID1A knockdown was determined by RT-qPCR and western blotting. The proliferation and apoptosis capacity was examined by colony formation, MTT proliferation, Annexin V-APC cell apoptosis and cell cycle analysis. RESULTS: ARID1A was lower in endometrial cancer cells and endometrial carcinoma tissue than in normal endometrial cells and benign endometrium (p<0.05). Small interfering RNA (siRNA)-ARID1A were transfected into HEC-1-A cells and we observed reduced cell growth and proliferation, increased apoptosis, and a significantly increased proportion of cells in the G2/M phase. CONCLUSION: Our results suggest that ARID1A mutation in endometrial cancer helped cell proliferation and inhibited cell apoptosis and also caused cell cycle arrest at the G2/M phase.
ARID1A is a tumor suppressor gene involved in chromatin remodelling. ARID1A mutations and loss of protein expression occur commonly in endometrioid and gynecological clear cell carcinoma where they are associated with mismat
ch repair (MMR) deficiency. We assessed ARID1A expression in a large cohort of colorectal carcinomas (CRCs). Immunohistochemistry for ARID1A was performed on whole sections from 100 CRCs and on 1876 CRCs in tissue microarray format. There was complete concordance between the staining on whole slides and tissue microarray sections. Loss of staining was found in 110 (5.9%) of 1876 CRCs and was strongly associated with older age, right sided location, large size, BRAF V600E mutation, MMR deficiency, high histological grade and medullary morphology, (all P < .01). There was a trend towards loss of expression being more common in females (P = .06). When subclassified by combined BRAF V600E mutation and MMR status, loss of ARID1A expression was found most commonly in CRCs with the BRAF V600E mutated, MMR- deficient phenotype (58 of 232 cases, 25%, P < .01). In univariate and multivariate analysis, loss of ARID1A expression was not associated with overall survival-hazard ratio 1.05 (0.68-1.64) and 0.60 (0.24-1.44), respectively. All carcinomas arising in patients with known Lynch syndrome (n = 12) were ARID1A positive. We conclude that loss of ARID1A expression occurs in a small but significant proportion of CRCs where it is strongly correlated with mismatch repair deficiency and other clinical and pathological features associated with somatic hypermethylation.
PURPOSE: The AT-rich interactive domain 1A (ARID1A) gene encodes BRG1-associated factor 250a, a component of the SWItch/Sucrose NonFermentable chromatin remodeling complex, which is considered a tumor suppressor in many tumors. We aimed to investigate
the prognostic significance of ARID1A expression in gastric cancers and explore its relationship with clinicopathologic parameters such as mismatch repair protein expression. MATERIALS AND METHODS: Four tissue microarrays were constructed from 191 resected specimens obtained at Soonchunhyang University Cheonan Hospital from 2006 to 2008. Nuclear expression of ARID1A was semiquantitatively assessed and binarized into retained and lost expression. RESULTS: Loss of ARID1A expression was observed in 62 cases (32.5%). This was associated with more frequent vascular invasion (P=0.019) and location in the upper third of the stomach (P=0.001), and trended toward more poorly differentiated subtypes (P=0.054). ARID1A loss was significantly associated with the mismatch repair-deficient phenotype (P=0.003). ARID1A loss showed a statistically significant correlation with loss of MLH1 (P=0.001) but not MSH2 expression (P=1.000). Kaplan-Meier survival analysis showed no statistically significant difference in overall survival; however, patients with retained ARID1A expression tended to have better overall survival than those with loss of ARID1A expression (P=0.053). In both mismatch repair-deficient and mismatch repair-proficient groups, survival analysis showed no differences related to ARID1A expression status. CONCLUSIONS: Our results demonstrated that loss of ARID1A expression is closely associated with the mismatch repair-deficient phenotype, especially in sporadic microsatellite instability-high gastric cancers.
Esophageal adenocarcinoma often presents at an advanced stage and has a dismal prognosis. Current prognostic markers have limited utility. ARID1A is implicated as a tumor suppressor gene in esophageal adenocarcinoma. Loss of ARID1A
expression correlates with DNA mismatch repair (MMR) protein deficiency in other tumors. We hypothesized that ARID1A loss is associated with prognosis and DNA MMR protein deficiency in esophageal adenocarcinoma. Tissue microarrays representing 316 surgically resected esophageal adenocarcinomas without neoadjuvant treatment were evaluated for ARID1A and MMR proteins by immunohistochemistry. Loss of ARID1A expression (ARID1A-loss) was detected in 41 of 316 (13%) adenocarcinomas. MMR deficiency was identified in 5% (17/316) but was detected more frequently in ARID1A-loss adenocarcinomas (13/41, 32%) than in ARID1A-retained adenocarcinomas (4/275, 1%; P < .001). Morphologically, ARID1A-loss adenocarcinomas frequently demonstrated peritumoral lymphoid aggregates (90%) and tumor infiltrating lymphocytes (51%). In patients with locally advanced or metastatic disease (stages III or IV, N = 169), patients with ARID1A-loss adenocarcinomas (N = 22) had longer overall survival than patients with ARID1A-retained adenocarcinomas (median [month]: 26 vs. 16, P = .010). In these patients, ARID1A-loss correlated with a 56% reduction in mortality independent of other prognostic factors (P = .007). In summary, loss of ARID1A expression is associated with DNA MMR protein deficiency in esophageal adenocarcinoma. Furthermore, ARID1A loss is independently associated with a more favorable prognosis for patients with locally advanced or metastatic esophageal adenocarcinomas.
Han N, etal., Appl Immunohistochem Mol Morphol. 2016 May-Jun;24(5):320-5. doi: 10.1097/PAI.0000000000000199.
The AT-rich interactive domain 1A (ARID1A) gene encodes a member of the switch/sucrose nonfermentable (SWI-SNF) chromatin remodeling complex, and is considered to work as a tumor suppressor in concert with p53. We investigated the clinical significance of ARID1A
style='font-weight:700;'>ARID1A protein expression in gastric cancer (GC), and examined its association with Epstein-Barr virus-associated (EBV) GC, mismatch repair (MMR) deficiency, and p53 alteration. We performed immunohistochemistry for ARID1A in 417 GC specimens using tissue microarray. EBV infection was examined using EBV-encoded small RNA in situ hybridization. Evaluation of MMR protein deficiency and p53 alteration was performed using immunohistochemistry, and microsatellite instability status was also assessed. Loss of ARID1A expression was observed in 21.1% of GC (88/417), but was not observed in gastric adenoma tissues or non-neoplastic gastric mucosa tissues. Loss of ARID1A showed positive correlations with advanced pTNM stage and tumor invasion (P=0.029 and 0.001, respectively). Overall survival was significantly influenced by the loss of ARID1A expression in wild-type p53 group (P=0.016, log-rank test). Moreover, ARID1A loss was significantly associated with EBV positivity, loss of MMR protein expression, and microsatellite instability high status (P=0.028, <0.001, and 0.011, respectively). All of the results from our cohort were verified using data from the Cancer Genome Atlas. In conclusion, loss of ARID1A is more common in advanced GC and is related to EBV positivity and MMR deficiency.
Genomic analyses have recently discovered the malignant subtype of human intrahepatic cholangiocarcinoma (ICC) characterized by frequent mutations of chromatin remodeling gene ARID1A; however, the biological and molecular functions still remain obscure. We here
examined the clinical and biological significances of ARID1A deficiency in human ICC. Immunohistochemical analysis demonstrated that the loss of ARID1A was an independent prognostic factor for overall survival of ICC patients (P = 0.023). We established ARID1A-knockout (KO) cells by using the CRISPR/Cas9 system from two human cholangiocarcinoma cell lines. ARID1A-KO cells exhibited significantly enhanced migration, invasion, and sphere formation activity. Microarray analysis revealed that ALDH1A1, a stemness gene, was the most significantly elevated genes in ARID1A-KO cells. In addition, ALDH enzymatic activity as a hallmark of cancer stem cells was markedly high in the KO cells. ARID1A and histone deacetylase 1 were directly recruited to the ALDH1A1 promoter region in cholangiocarcinoma cells with undetectable ALDH1A1 expression by chromatin immunoprecipitation assay. The histone H3K27 acetylation level at the ALDH1A1 promoter region was increased in cells when ARID1A was disrupted (P < 0.01). Clinically, inverse correlation between ARID1A and ALDH1A1 expression was also identified in primary ICC (P = 0.018), and ARID1A-negative and ALDH1A1-positve ICCs showed worse prognosis than only ARID1A-negative cases (P = 0.002). In conclusion, ARID1A may function as a tumor suppressor in ICC through transcriptional downregulation of ALDH1A1 expression with decreasing histone H3K27 acetylation. Our studies provide the basis for the development of new epigenetic approaches to ARID1A-negative ICC. Immunohistochemical loss of ARID1A is an independent prognostic factor in intrahepatic cholangiocarcinoma patients. ARID1A recruits HDAC1 to the promoter region of ALDH1A1, a stemness gene, and epigenetically suppresses ALDH1A1 expression with decreasing histone H3K27 acetylation in cholangiocarcinoma cells.
Schallenberg S, etal., BMC Cancer. 2020 Jan 6;20(1):12. doi: 10.1186/s12885-019-6425-3.
BACKGROUND: The SWI/SNF complex is an important chromatin remodeler, commonly dysregulated in cancer, with an estimated mutation frequency of 20%. ARID1A is the most frequently mutated subunit gene. Almost nothing is known about the other familiar mem
bers of the SWI/SNF complexes, SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1), in oesophageal adenocarcinoma (EAC). METHODS: We analysed a large cohort of 685 patients with EAC. We used four different antibodies to detect a loss-of-protein of ARID1A BRM, BRG1 and INI1 by immunohistochemistry and correlated these findings with molecular and clinical data. RESULTS: Loss of ARID1A, BRG1, BRM and INI1 was observed in 10.4, 3.4, 9.9 and 2% of EAC. We found a co-existing protein loss of ARID1A and BRM in 9.9% and of ARID1A and BRG1 in 2.2%. Patients with loss of ARID1A and TP53 wildtype EACs showed a shortened overall survival compared with AIRDA1A-positive tumours [median overall survival was 60.1 months (95%CI 1.2-139.9 months)] in patients with ARIDA-1A expression and 26.2 months (95%CI 3.7-19.1 months) in cases of ARIDA-1A loss (p = 0.044). Tumours with loss or expression of ARID1A and TP53 loss were not associated with a difference in survival. Only one tumour revealed high microsatellite instability (MSI-H) with concomitant ARID1A loss. All other ARID1A loss-EACs were microsatellite-stable (MSS). No predictive relevance was seen for SWI/SNF-complex alterations and simultaneous amplification of different genes (PIK3CA, KRAS, c-MYC, MET, GATA6, ERBB2). CONCLUSION: Our work describes, for the first time, loss of one of the SWI/SNF ATPase subunit proteins in a large number of adenocarcinomas of the oesophagus. Several papers discuss possible therapeutic interventions for tumours showing a loss of function of the SWI/SNF complex, such as PARP inhibitors or PI3K and AKT inhibitors. Future studies will be needed to show whether SWI/SNF complex-deficient EACs may benefit from personalized therapy.
Streppel MM, etal., Oncogene. 2014 Jan 16;33(3):347-57. doi: 10.1038/onc.2012.586. Epub 2013 Jan 14.
The incidence of Barrett's esophagus (BE)-associated esophageal adenocarcinoma (EAC) is increasing. Next-generation sequencing (NGS) provides an unprecedented opportunity to uncover genomic alterations during BE pathogenesis and progression to EAC, but treatment-naive surgical specimens are scarce.
The objective of this study was to establish the feasibility of using widely available endoscopic mucosal biopsies for successful NGS, using samples obtained from a BE 'progressor'. Paired-end whole-genome NGS was performed on the Illumina platform using libraries generated from mucosal biopsies of normal squamous epithelium (NSE), BE and EAC obtained from a patient who progressed to adenocarcinoma during endoscopic surveillance. Selective validation studies, including Sanger sequencing, immunohistochemistry and functional assays, were performed to confirm the NGS findings. NGS identified somatic nonsense mutations of AT-rich interactive domain 1A (SWI like) (ARID1A) and PPIE and an additional 37 missense mutations in BE and/or EAC, which were confirmed by Sanger sequencing. ARID1A mutations were detected in 15% (3/20) high-grade dysplasia (HGD)/EAC patients. Immunohistochemistry performed on an independent archival cohort demonstrated ARID1A protein loss in 0% (0/76), 4.9% (2/40), 14.3% (4/28), 16.0% (8/50) and 12.2% (12/98) of NSE, BE, low-grade dysplasia, HGD and EAC tissues, respectively, and was inversely associated with nuclear p53 accumulation (P=0.028). Enhanced cell growth, proliferation and invasion were observed on ARID1A knockdown in EAC cells. In addition, genes downstream of ARID1A that potentially contribute to the ARID1A knockdown phenotype were identified. Our studies establish the feasibility of using mucosal biopsies for NGS, which should enable the comparative analysis of larger 'progressor' versus 'non-progressor' cohorts. Further, we identify ARID1A as a novel tumor-suppressor gene in BE pathogenesis, reiterating the importance of aberrant chromatin in the metaplasia-dysplasia sequence.
Yang F, etal., Cell Death Dis. 2018 Jan 9;9(1):12. doi: 10.1038/s41419-017-0020-9.
Infection with Helicobacter pylori (H. pylori) and the resulting gastric inflammation is regarded as the strongest risk factor for gastric carcinogenesis and progression. NF-κB plays an important role in linking H. pylori-mediated inflammation to cancer. However, the underlying mechanisms are
poorly understood. In this study, we find that H. pylori infection induces miR-223-3p expression in H. pylori CagA-dependent manner. NF-κB stimulates miR-223-3p expression via directly binding to the promoter of miR-223-3p and is required for H. pylori CagA-mediated upregulation of miR-223-3p. miR-223-3p promotes the proliferation and migration of gastric cancer cells by directly targeting ARID1A and decreasing its expression. Furthermore, miR-223-3p/ARID1A axis is involved in CagA-induced cell proliferation and migration. In the clinical setting, the level of miR-223-3p is upregulated, while ARID1A is downregulated significantly in human gastric cancer tissues compared with the corresponding noncancerous tissues. The expression level of miR-223-3p is significantly higher in H. pylori-positive gastric cancer tissues than that in H. pylori-negative tissues. Moreover, a negative correlation between miR-223-3p and ARID1A expression is found in the gastric cancer tissues. Taken together, our findings suggested NF-κB/miR-223-3p/ARID1A axis may link the process of H. pylori-induced chronic inflammation to gastric cancer, thereby providing a new insight into the mechanism underlying H. pylori-associated gastric diseases.
Yan HB, etal., Carcinogenesis. 2014 Apr;35(4):867-76. doi: 10.1093/carcin/bgt398. Epub 2013 Nov 30.
The chromatin remodeling gene AT-rich interactive domain-containing protein 1A (ARID1A) encodes the protein BAF250a, a subunit of human SWI/SNF-related complexes. Recent studies have identified ARID1A as a tumor suppressor.
Here, we show that ARID1A expression is reduced in gastric cancer (GC) tissues, which are significantly associated with local lymph node metastasis, tumor infiltration and poor patient prognosis. ARID1A silencing enforces the migration and invasion of GC cells, whereas ectopic expression of ARID1A inhibits migration. The adhesive protein E-cadherin is remarkably downregulated in response to ARID1A silencing, but it is upregulated by ARID1A overexpression. E-cadherin overexpression significantly inhibits GC cell migration and invasion, whereas CDH1 (coded E-cadherin) silencing promotes migration. Restored expression of CDH1 in ARID1A-silenced cell lines restores the inhibition of cell migration. Luciferase reporter assays and chromatin immunoprecipitation indicate that the ARID1A-associated SWI/SNF complex binds to the CDH1 promoter and modulates CDH1 transcription. ARID1A knockdown induces evident morphological changes of GC cells with increased expression of mesenchymal markers, indicating an epithelial-mesenchymal transition. ARID1A silencing does not alter the level of β-catenin but induces a subcellular redistribution of β-catenin from the plasma membrane to the cytoplasm and nucleus. Immunohistochemical studies demonstrate that reduced expression of E-cadherin is associated with local lymph node metastasis, tumor infiltration and poor clinical prognosis. ARID1A and E-cadherin expression show a strong correlation in 75.4% of the analyzed GC tissues. They are synergistically downregulated in 23.5% of analyzed GC tissues. In conclusion, ARID1A targets E-cadherin during the modulation of GC cell migration and invasion.
