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Molecular and Cellular Pathobiology

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

Hamza Chettouh, Laetitia Fartoux, Lynda Aoudjehane, Dominique Wendum, Audrey Clapéron, Yves Chrétien, Colette Rey, Olivier Scatton, Olivier Soubrane, Filomena Conti, Françoise Praz, Chantal Housset, Olivier Rosmorduc and Christèle Desbois-Mouthon
Hamza Chettouh
Authors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, France
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Laetitia Fartoux
Authors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, France
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Lynda Aoudjehane
Authors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, France
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Dominique Wendum
Authors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, France
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Audrey Clapéron
Authors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, France
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Yves Chrétien
Authors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, France
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Colette Rey
Authors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, France
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Olivier Scatton
Authors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, France
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Olivier Soubrane
Authors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, France
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Filomena Conti
Authors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, France
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Françoise Praz
Authors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, France
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Chantal Housset
Authors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, France
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Olivier Rosmorduc
Authors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, France
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Christèle Desbois-Mouthon
Authors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, FranceAuthors' Affiliations: INSERM UMR_S 938, Centre de Recherche Saint-Antoine; UPMC Univ Paris 06, UMR_S 938; Hépatologie, Anatomie et cytologie pathologiques, and Chirurgie hépato-biliaire et transplantation hépatique, Hôpital Saint-Antoine, AP-HP; and Human HepCell, Hôpital Saint-Antoine, Paris, France
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DOI: 10.1158/0008-5472.CAN-12-3824 Published July 2013
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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.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received October 3, 2012.
  • Revision received February 20, 2013.
  • Accepted March 21, 2013.
  • ©2013 American Association for Cancer Research.
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Cancer Research: 73 (13)
July 2013
Volume 73, Issue 13
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Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors
Hamza Chettouh, Laetitia Fartoux, Lynda Aoudjehane, Dominique Wendum, Audrey Clapéron, Yves Chrétien, Colette Rey, Olivier Scatton, Olivier Soubrane, Filomena Conti, Françoise Praz, Chantal Housset, Olivier Rosmorduc and Christèle Desbois-Mouthon
Cancer Res July 1 2013 (73) (13) 3974-3986; DOI: 10.1158/0008-5472.CAN-12-3824

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Mitogenic Insulin Receptor-A Is Overexpressed in Human Hepatocellular Carcinoma due to EGFR-Mediated Dysregulation of RNA Splicing Factors
Hamza Chettouh, Laetitia Fartoux, Lynda Aoudjehane, Dominique Wendum, Audrey Clapéron, Yves Chrétien, Colette Rey, Olivier Scatton, Olivier Soubrane, Filomena Conti, Françoise Praz, Chantal Housset, Olivier Rosmorduc and Christèle Desbois-Mouthon
Cancer Res July 1 2013 (73) (13) 3974-3986; DOI: 10.1158/0008-5472.CAN-12-3824
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