Insulin receptor isoform A favors tumor progression in human hepatocellular carcinoma by increasing stem/progenitor cell features. (28th May 2019)

• Record Type: Journal Article
• Authors: Benabou, Eva; Salamé, Zeina; Wendum, Dominique; Lequoy, Marie; Tahraoui, Sylvana; Merabtene, Fatiha; Chrétien, Yves; Scatton, Olivier; Rosmorduc, Olivier; Fouassier, Laura; Fartoux, Laetitia; Praz, Françoise; Desbois-Mouthon, Christèle
• Is Part Of: Cancer letters. Volume 450(2019)
• Page Start: 155
• Page End: 168
• Publication Date: 2019-05-28
• Subjects: Liver cancer -- INSR -- Invasion -- Cytokeratin-19; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.02.037
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Hepatocellular carcinoma (HCC) is one of the most common and deadly neoplasms. Insulin receptor (IR) exists in two isoforms, IR-A and IR-B, the latter being predominantly expressed in normal adult hepatocytes while IR-A is overexpressed in HCC to the detriment of IR-B. This study evaluated the biological functions associated with IR-A overexpression in HCC in relation to expression of its ligand IGF-II. The value of INSRA:INSRB ratio which was increased in˜ 70% of 85 HCC was associated with stem/progenitor cell features such as cytokeratin-19 and α-fetoprotein and correlated with shorter patient survival. IGF2 mRNA upregulation was observed in 9.4% of HCC and was not associated with higher INSRA:INSRB ratios. Ectopic overexpression of IR-A in two HCC cell lines presenting a strong autocrine IGF-II secretion loop or not stimulated cell migration and invasion. In cells cultured as spheroids, IR-A overexpression promoted gene programs related to stemness, inflammation and cell movement. IR-A also increased cell line tumorigenicity in vivo after injection to immunosuppressed mice and the sphere-forming cells made a significant contribution to this effect. Altogether, these results demonstrate that IR-A is a novel player in HCC progression. Highlights: Increased INSRA:INSRB ratio in HCC is associated with aggressiveness markers and poor prognosis. IR-A overexpression promotes gene programs related to migration/invasion, inflammation and stem/progenitor cell features. The stem/progenitor cell contingent contributes to the promotion of tumorigenesis induced by IR-A. The presence of an autocrine IGF-II loop is not mandatory for the pro-tumorigenic effects of IR-A.