Pin1: a novel regulator of tumor angiogenesis and invasiveness in hepatocellular carcinoma

Abstract

Objective: Hepatocellular carcinoma (HCC) is a highly-vascularized tumour with rapid growth and frequent vascular invasion. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that plays a crucial role in tumor angiogenesis, and has been shown to contribute to HCC invasiveness and metastasis. However, the regulation of VEGF in HCC has not been well defined. We have previously shown that the peptidyl prolyl isomerase Pin1 is frequently over-expressed in HCC and plays an important role in hepatocarcinogenesis; furthermore, suppression of Pin1 decreased HCC tumourigenesis in vivo. In this study, we investigated the expression of Pin1 and VEGF in HCC tumor samples, and the potential role of Pin1 in VEGF-induced angiogenesis.

Methodolgy and Results: In clinical specimens of HCC, Pin1 over-expression positively correlated with VEGF expression (p<0.001), and there was a positive correlation between Pin1 over-expression and tumour angiogenesis, as assessed by microvessel density (MVD). Using two HCC cell lines of high and low metastatic potentials, MHCC-97H and MHCC-97L respectively, we found that significantly higher levels of Pin 1 was expressed in MHCC-97H compared with MHCC-97L. Moreover, enforced expression of Pin1 in MHCC-97L greatly enhanced the invasiveness of these cells, accompanied with an increase in VEGF expression. Conversely, suppression of Pin1 levels in MHCC-97H reduced the invasiveness of these cells, with concurrent down-regulation of VEGF expression. Ectopic Pin1 transfection into a non-metastatic HCC cell line Hep3B also increased VEGF expression. Furthermore, Pin1 induced transcriptional activation of VEGF through up-regulation of hypoxia-inducible factor-1α (HIF-1α) expression.

Conclusion: This study uncovered a novel role of Pin1 in the regulation of VEGF to promote HCC angiogenesis and invasiveness, providing a new therapeutic target for development of inhibitors of angiogenesis in this highly vascular tumor.