RGD Reference Report - Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors. - Rat Genome Database

Send us a Message
Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   
Search RGD Grant Resources Citing RGD About Us Contact Us
Genes Variants Community Projects QTLs Strains Markers Genome Information Ontologies Cell Lines References Download Submit Data
OntoMate (Literature Search) JBrowse (Genome Browser) Synteny Browser (VCMap) Variant Visualizer Multi-Ontology Enrichment (MOET) Gene-Ortholog Location Finder (GOLF) InterViewer (Protein-Protein Interactions) PhenoMiner (Quatitative Phenotypes) Gene Annotator OLGA (Gene List Generator) AllianceMine GViewer (Genome Viewer)
Aging & Age-Related Disease Cancer & Neoplastic Disease Cardiovascular Disease Coronavirus Disease Developmental Disease Diabetes Hematologic Disease Immune & Inflammatory Disease Infectious Disease Liver Disease Neurological Disease Obesity & Metabolic Syndrome Renal Disease Respiratory Disease Sensory Organ Disease
Find Models   new Genetic Models Autism Models Rat PhenoMiner (Quantitative Phenotypes) Chinchilla PhenoMiner Expected Ranges (Quantitative Phenotype) PhenoMiner Term Comparison Hybrid Rat Diversity Panel Phenotypes Phenotypes in Other Animal Models Animal Husbandry Strain Medical Records Phylogenetics Strain Availability Calendar Rats 101 Submissions Photo Archive
Pathways
Rat Community Forum Directory of Rat Laboratories Video Tutorials News RGD Publications RGD Presentations Archive Nomenclature Guidelines Resource Links Laboratory Resources Employment Resources

Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors.

Authors: Chettouh, H  Fartoux, L  Aoudjehane, L  Wendum, D  Claperon, A  Chretien, Y  Rey, C  Scatton, O  Soubrane, O  Conti, F  Praz, F  Housset, C  Rosmorduc, O  Desbois-Mouthon, C 
Citation: Chettouh H, etal., Cancer Res. 2013 Jul 1;73(13):3974-86. doi: 10.1158/0008-5472.CAN-12-3824. Epub 2013 Apr 30.
RGD ID: 9685423
Pubmed: PMID:23633480   (View Abstract at PubMed)
DOI: DOI:10.1158/0008-5472.CAN-12-3824   (Journal Full-text)

Insulin receptor (IR) exists as two isoforms resulting from the alternative splicing of IR pre-mRNA. IR-B promotes the metabolic effects of insulin, whereas IR-A rather signals proliferative effects. IR-B is predominantly expressed in the adult liver. Here, we show that the alternative splicing of IR pre-mRNA is dysregulated in a panel of 85 human hepatocellular carcinoma (HCC) while being normal in adjacent nontumor liver tissue. An IR-B to IR-A switch is frequently observed in HCC tumors regardless of tumor etiology. Using pharmacologic and siRNA approaches, we show that the autocrine or paracrine activation of the EGF receptor (EGFR)/mitogen-activated protein/extracellular signal-regulated kinase pathway increases the IR-A:IR-B ratio in HCC cell lines, but not in normal hepatocytes, by upregulating the expression of the splicing factors CUGBP1, hnRNPH, hnRNPA1, hnRNPA2B1, and SF2/ASF. In HCC tumors, there is a significant correlation between the expression of IR-A and that of splicing factors. Dysregulation of IR pre-mRNA splicing was confirmed in a chemically induced model of HCC in rat but not in regenerating livers after partial hepatectomy. This study identifies a mechanism responsible for the generation of mitogenic IR-A and provides a novel interplay between IR and EGFR pathways in HCC. Increased expression of IR-A during neoplastic transformation of hepatocytes could mediate some of the adverse effects of hyperinsulinemia on HCC.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hepatocellular carcinoma  IEP 9685423; 9685423protein:increased expression:liver (human)RGD 
hepatocellular carcinoma  ISOHnrnpa2b1 (Rattus norvegicus)9685423; 9685423mRNA:increased expression:liver (rat)RGD 
hepatocellular carcinoma  ISOHNRNPA1 (Homo sapiens)9685423; 9685423protein:increased expression:liver (human)RGD 
hepatocellular carcinoma  IEP 9685423mRNA:increased expression:liver (rat)RGD 
hepatocellular carcinoma  ISOHNRNPH1 (Homo sapiens)9685423; 9685423protein:increased expression:liver (human)RGD 
hepatocellular carcinoma  IEP 9685423; 9685423mRNA more ...RGD 
hepatocellular carcinoma  ISOInsr (Rattus norvegicus) and INSR (Homo sapiens)9685423mRNA more ...RGD 
hepatocellular carcinoma  ISOSrsf1 (Rattus norvegicus)9685423; 9685423mRNA:increased expression:liver (human)RGD 
hepatocellular carcinoma  IEP 9685423mRNA:increased expression:liver (human)RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
liver regeneration  IEP 9685423; 9685423 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hnrnpa1  (heterogeneous nuclear ribonucleoprotein A1)
Hnrnpa2b1  (heterogeneous nuclear ribonucleoprotein A2/B1)
Hnrnph1  (heterogeneous nuclear ribonucleoprotein H1)
Insr  (insulin receptor)
Srsf1  (serine and arginine rich splicing factor 1)

Genes (Mus musculus)
Hnrnpa1  (heterogeneous nuclear ribonucleoprotein A1)
Hnrnpa2b1  (heterogeneous nuclear ribonucleoprotein A2/B1)
Hnrnph1  (heterogeneous nuclear ribonucleoprotein H1)
Insr  (insulin receptor)
Srsf1  (serine and arginine-rich splicing factor 1)

Genes (Homo sapiens)
HNRNPA1  (heterogeneous nuclear ribonucleoprotein A1)
HNRNPA2B1  (heterogeneous nuclear ribonucleoprotein A2/B1)
HNRNPH1  (heterogeneous nuclear ribonucleoprotein H1)
INSR  (insulin receptor)
SRSF1  (serine and arginine rich splicing factor 1)


Additional Information