TRIP6 promotes tumorigenic capability through regulating FOXC1 in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is an aggressive malignant tumor with poor prognosis that is characterized by high rates of postoperative recurrence and mortality. Understanding the molecular mechanism of this malignancy is of great significance for the development of new and effective strategies for the treatment of hepatocellular carcinoma. Thyroid hormone receptor-interacting protein 6 (TRIP6), also known as zyxin-related protein-1 or ZRP-1, is an adaptor protein that belongs to the zyxin family of LIM proteins. Recent studies showed that TRIP6 is involved in carcinogenesis. But the functional role of TRIP6 in HCC has not been reported to date.

Methods: TRIP6 expression level in HCC cell lines and normal cell line was measured by qPCR. The roles of TRIP6 on HCC cell proliferation, colony formation, and invasion were examined by MTT assay, colony formation assay, and transwell invasion assay, respectively. The effect of TRIP6 on the overall survival of HCC patients was further analyzed. ChIP assay and western blot were performed to validate whether FOXC1 was involved in the regulation of TRIP6 expression.

Results: Western blot and immunohistochemical analyses showed that TRIP6 expression was up-regulated in HCC tissues compared with adjacent non-tumor tissues. Kaplan-Meier survival analysis indicated that upregulation of TRIP6 was dramatically associated with poor overall survival. TRIP6 knockdown significantly inhibited cell migration, invasion, and proliferation, and its effect on cell proliferation was mediated by the modulation of cell cycle progression. FOXC1 also played a vital role in TRIP6 regulation. TRIP6 mediated the FOXC1-regulated proliferation, invasion, and migration in vitro and tumor growth in vivo.

Conclusions: These results suggest that TRIP6 may contribute to the invasiveness and metastasis of HCC cells, and provide new insight into the crucial role of TRIP6 in tumorigenesis and cancer progression.