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

Cancer Res. 2013 Jul 1;73(13):3974-86. doi: 10.1158/0008-5472.CAN-12-3824. Epub 2013 Apr 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics*
  • Antigens, CD / metabolism
  • CELF1 Protein
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Transformation, Neoplastic / metabolism
  • ErbB Receptors / metabolism*
  • Gene Expression
  • Gene Expression Regulation, Neoplastic*
  • 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 Neoplasms, Experimental / metabolism*
  • 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 / genetics*
  • Receptor, Insulin / metabolism
  • Serine-Arginine Splicing Factors


  • Antigens, CD
  • CELF1 Protein
  • CELF1 protein, human
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Hnrnpa1 protein, rat
  • Insulin
  • Nuclear Proteins
  • Protein Isoforms
  • RNA, Messenger
  • RNA-Binding Proteins
  • SRSF3 protein, human
  • hnRNP A2
  • hnRNPA1 protein, human
  • Serine-Arginine Splicing Factors
  • Insulin-Like Growth Factor II
  • ErbB Receptors
  • INSR protein, human
  • Receptor, Insulin