Insulin-Like Growth Factor Binding Protein-2 Promotes Proliferation and Predicts Poor Prognosis in Hepatocellular Carcinoma.

Abstract

BackgroundInsulin-like growth factor binding protein-2 (IGFBP2) levels are significantly increased in the plasma of hepatocellular carcinoma (HCC) patients. However, the correlation between IGFBP2 levels and clinical parameters and the exact role of IGFBP2 in HCC are unclear. In this study, we identified the role and potential molecular mechanisms of IGFBP2 in HCC.Materials and MethodsELISA assays were used to detect plasma IGFBP2 levels in HCC patients and healthy controls, and the correlations with patients’ clinicopathological data were analyzed. The CCK8 assay was used to explore cell proliferation. Luciferase reporter, co-immunoprecipitation, and immunofluorescence assays were used to demonstrate the molecular mechanism of IGFBP2 in HCC.ResultsPlasma IGFBP2 levels were determined blindly in 37 HCC patients and 37 matched healthy controls. The mean plasma IGFBP2 concentrations in HCC patients were higher than in healthy controls, and IGFBP2 levels in HCC were positively correlated with the degree of differentiation, tumor size, metastasis, and portal venous invasion. Exogenous IGFBP2 activated integrin β1 and thus induced the combination and colocalization of activated integrin β1 and p-FAK, which promoted the phosphorylation of FAK, Erk, and Elk1, eventually inducing EGR1-mediated proliferation of the HCC cell lines HepG2 and HCCLM3. Meanwhile, neutralization of integrin β1 inhibited IGFBP2-induced FAK, Erk, Elk1, and EGR1 activation.ConclusionTaken together, these results indicated that exogenous IGFBP2 promoted the integrin β1/FAK/Erk/Elk1/EGR1 pathway, which stimulated the proliferation of HCC cells. Plasma IGFBP2 could be a novel prognostic biomarker for HCC patients.