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.
Highlights
Recent epidemiologic data showing that hyperinsulinemia is a risk factor for a variety of malignancies has renewed the interest for studies examining insulin receptor (IR) signaling in cancer development [1,2,3]
Total IR mRNA expression was similar between nontumor liver tissues and healthy livers, whereas it was significantly higher in Hepatocellular carcinoma (HCC) tumors compared with matched nontumor tissues (Fig. 1A)
Standard PCR experiments using primers for the flanking exons 10 and 12 combined with agarose gel electrophoresis showed that IR-A mRNA was detected in tumors but not in adjacent nontumor tissues, whereas IR-B mRNA expression was decreased in tumors in comparison with adjacent nontumor tissues (Fig. 1D)
Summary
Recent epidemiologic data showing that hyperinsulinemia is a risk factor for a variety of malignancies has renewed the interest for studies examining insulin receptor (IR) signaling in cancer development [1,2,3]. Dysregulations of IR expression and/or downstream signaling have been reported in cancers [4, 5]. Hepatocellular carcinoma (HCC), which is the most common primary liver tumor, is no exception. Elevated insulin levels in serum have been shown to be predictive of HCC recurrence in hepatitis C virus (HCV) and hepatitis B virus (HBV) carriers [6, 7]. The use of exogenous insulin or of insulin secretagogues might increase the risk of HCC. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Authors' Affiliations: 1INSERM UMR_S 938, Centre de Recherche SaintAntoine; 2UPMC Univ Paris 06, UMR_S 938; 3Hepatologie, 4Anatomie et cytologie pathologiques, and 5Chirurgie hepato-biliaire et transplantation hepatique, Ho^pital Saint-Antoine, AP-HP; and 6Human HepCell, Ho^pital Saint-Antoine, Paris, France
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