1. Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors.
- Author
-
Chettouh H, Fartoux L, Aoudjehane L, Wendum D, Clapéron A, Chrétien Y, Rey C, Scatton O, Soubrane O, Conti F, Praz F, Housset C, Rosmorduc O, and Desbois-Mouthon C
- Subjects
- Animals, Antigens, CD metabolism, CELF1 Protein, Cell Transformation, Neoplastic metabolism, Gene Expression, Hep G2 Cells, Hepatocytes metabolism, Heterogeneous Nuclear Ribonucleoprotein A1, Heterogeneous-Nuclear Ribonucleoprotein Group A-B genetics, Heterogeneous-Nuclear Ribonucleoprotein Group A-B metabolism, Humans, Insulin physiology, Insulin-Like Growth Factor II physiology, Liver Regeneration, MAP Kinase Signaling System, Nuclear Proteins genetics, Nuclear Proteins metabolism, Protein Isoforms genetics, Protein Isoforms metabolism, RNA Splicing, RNA, Messenger genetics, RNA, Messenger metabolism, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Rats, Receptor, Insulin metabolism, Serine-Arginine Splicing Factors, Antigens, CD genetics, Carcinoma, Hepatocellular metabolism, ErbB Receptors metabolism, Gene Expression Regulation, Neoplastic, Liver Neoplasms, Experimental metabolism, Receptor, Insulin genetics
- Abstract
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., (©2013 AACR.)
- Published
- 2013
- Full Text
- View/download PDF