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Cancer Lett ; 450: 155-168, 2019 05 28.
Article in English | MEDLINE | ID: mdl-30849481

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.


Subject(s)
Antigens, CD/metabolism , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , Neoplastic Stem Cells/pathology , Receptor, Insulin/metabolism , Animals , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Disease Progression , Female , Heterografts , Humans , Immunohistochemistry , Liver Neoplasms/pathology , Mice , Mice, Inbred NOD , Mice, Nude , Mice, SCID , Neoplastic Stem Cells/metabolism , Protein Isoforms
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