title: Mitogenic insulin receptor-A is overexpressed in human hepatocellular carcinoma due to EGFR-mediated dysregulation of RNA splicing factors.
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.
authors: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938, Paris, France.
authors: Hamza
authors: H
authors: Chettouh
authors: Laetitia
authors: L
authors: Fartoux
authors: Lynda
authors: L
authors: Aoudjehane
authors: Dominique
authors: D
authors: Wendum
authors: Audrey
authors: A
authors: Clapéron
authors: Yves
authors: Y
authors: Chrétien
authors: Colette
authors: C
authors: Rey
authors: Olivier
authors: O
authors: Scatton
authors: Olivier
authors: O
authors: Soubrane
authors: Filomena
authors: F
authors: Conti
authors: Françoise
authors: F
authors: Praz
authors: Chantal
authors: C
authors: Housset
authors: Olivier
authors: O
authors: Rosmorduc
authors: Christèle
authors: C
authors: Desbois-Mouthon
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D000067879:CELF1 Protein; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology; D007335:Insulin-Like Growth Factor II / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D008115:Liver Regeneration; D020935:MAP Kinase Signaling System; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors
chemical_list: D015703:Antigens, CD; D000067879:CELF1 Protein; C102843:CELF1 protein, human; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C000619658:Hnrnpa1 protein, rat; D007328:Insulin; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C491388:SRSF3 protein, human; C439768:hnRNP A2; C000619656:hnRNPA1 protein, human; D000068103:Serine-Arginine Splicing Factors; D007335:Insulin-Like Growth Factor II; D066246:ErbB Receptors; C435941:INSR protein, human; D011972:Receptor, Insulin