RGD Reference Report - Differential regulation of MMPs by E2F1, Sp1 and NF-kappa B controls the small cell lung cancer invasive phenotype. - Rat Genome Database

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Differential regulation of MMPs by E2F1, Sp1 and NF-kappa B controls the small cell lung cancer invasive phenotype.

Authors: Li, Zunling  Guo, Yanxia  Jiang, Hanming  Zhang, Tingguo  Jin, Changzhu  Young, Charles Y F  Yuan, Huiqing 
Citation: Li Z, etal., BMC Cancer. 2014 Apr 22;14:276. doi: 10.1186/1471-2407-14-276.
RGD ID: 13464335
Pubmed: PMID:24755270   (View Abstract at PubMed)
PMCID: PMC4077048   (View Article at PubMed Central)
DOI: DOI:10.1186/1471-2407-14-276   (Journal Full-text)


BACKGROUND: E2F1 transcription factor plays a vital role in the regulation of diverse cellular processes including cell proliferation, apoptosis, invasion and metastasis. E2F1 overexpression has been demonstrated in small cell lung cancer (SCLC), and extensive metastasis in early phase is the most important feature of SCLC. In this study, we investigated the involvement of E2F1 in the process of invasion and metastasis in SCLC by regulating the expression of matrix metalloproteinases (MMPs).
METHODS: Immunohistochemistry was performed to evaluate the expression of E2F1 and MMPs in SCLC samples in a Chinese Han population. The impact of E2F1 on invasion and metastasis was observed by transwell and wound healing experiments with depletion of E2F1 by specific siRNA. The target genes regulated by E2F1 were identified by chromatin immunoprecipitation (ChIP)-to-sequence, and the expressions of target genes were detected by real time PCR and western blotting. The dual luciferase reporter system was performed to analyze the regulatory relationship between E2F1 and MMPs.
RESULTS: E2F1 is an independent and adverse prognosis factor that is highly expressed in SCLC in a Chinese Han population. Knockdown of E2F1 by specific siRNA resulted in the downregulation of migration and invasion in SCLC. The expressions of MMP-9 and -16 in SCLC were higher than other MMPs, and their expressions were most significantly reduced after silencing E2F1. ChIP-to-sequence and promoter-based luciferase analysis demonstrated that E2F1 directly controlled MMP-16 expression via an E2F1 binding motif in the promoter. Although one E2F1 binding site was predicted in the MMP-9 promoter, luciferase analysis indicated that this binding site was not functionally required. Further study demonstrated that E2F1 transcriptionally controlled the expression of Sp1 and p65, which in turn enhanced the MMP-9 promoter activity in SCLC cells. The associations between E2F1, Sp1, p65, and MMP-9 were validated by immunohistochemistry staining in SCLC tumors.
CONCLUSIONS: E2F1 acts as a transcriptional activator for MMPs and directly enhances MMP transcription by binding to E2F1 binding sequences in the promoter, or indirectly activates MMPs through enhanced Sp1 and NF-kappa B as a consequence of E2F1 activation in SCLC.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
E2F1Humanlung small cell carcinoma disease_progressionIEP  RGD 
E2f1Ratlung small cell carcinoma disease_progressionISOE2F1 (Homo sapiens) RGD 
E2f1Mouselung small cell carcinoma disease_progressionISOE2F1 (Homo sapiens) RGD 

Objects Annotated

Genes (Rattus norvegicus)
E2f1  (E2F transcription factor 1)

Genes (Mus musculus)
E2f1  (E2F transcription factor 1)

Genes (Homo sapiens)
E2F1  (E2F transcription factor 1)


Additional Information