Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors - Sorbonne Université Access content directly
Journal Articles Cancer Research Year : 2013

Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors

Hamza Chettouh
  • Function : Author
Laetitia Fartoux
  • Function : Author
Dominique Wendum
  • Function : Author
Audrey Clapéron
  • Function : Author
Yves Chrétien
  • Function : Author
Colette Rey
  • Function : Author
Olivier Scatton
  • Function : Author
Olivier Soubrane
  • Function : Author
Filomena Conti
  • Function : Author
Françoise Praz
  • Function : Author
Chantal Housset
  • Function : Author
Olivier Rosmorduc
  • Function : Author
Christèle Desbois-Mouthon
  • Function : Author

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. Cancer Res; 73(13); 3974–86. ©2013 AACR.
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hal-03979220 , version 1 (08-02-2023)

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Hamza Chettouh, Laetitia Fartoux, Lynda Aoudjehane, Dominique Wendum, Audrey Clapéron, et al.. Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors. Cancer Research, 2013, 73 (13), pp.3974-3986. ⟨10.1158/0008-5472.CAN-12-3824⟩. ⟨hal-03979220⟩
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