Abstract
BackgroundKindlin-2 is a member of the focal adhesion protein family that regulates invasion and metastasis in multiple malignancies; however, little is known about the role of Kindlin-2 in hepatocellular carcinoma (HCC) progression.MethodsImmunohistochemistry was used to investigate Kindlin-2 expression in 177 pairs of human HCC and adjacent liver tissue samples. The role of Kindlin-2 in the in vitro invasion and migration of HCC cell lines was evaluated in MHCC97H, LM3 and SMMC7721 cells. Microarray expression analysis was applied to explore the molecular mechanism through which Kindlin-2 promoted HCC progression. Quantitative real-time PCR and Western blotting were performed to verify the microarray results.ResultsHigh Kindlin-2 expression was found to significantly correlate with aggressive HCC clinicopathological features including tumor encapsulation, microvascular invasion, extrahepatic metastasis and poor prognosis. In vitro, Kindlin-2 knockout or knockdown inhibited HCC cell adhesion, migration and invasion, while ectopic Kindlin-2 expression promoted these processes. Importantly, Kindlin-2 activated Wnt/β-catenin signaling and increased β-catenin expression, especially levels of non-phosphorylated β-catenin, as well as two Wnt/β-catenin signaling pathway targets, Axin2 and MMP7. Kindlin-2 also induced a change in the expression profile of HCC cells, suggesting the cells underwent epithelial-mesenchymal transition. For example, the expression of the epithelial marker E-cadherin was downregulated, while the mesenchymal markers Vimentin, N-cadherin and Snail were upregulated.ConclusionKindlin-2 promotes HCC invasion, metastasis and epithelial-mesenchymal transition through Wnt/β-catenin signaling.
Highlights
Kindlin-2 is a member of the focal adhesion protein family that regulates invasion and metastasis in multiple malignancies; little is known about the role of Kindlin-2 in hepatocellular carcinoma (HCC) progression
The results showed that Kindlin-2 was localized in the cytoplasm of HCC cell lines
Compared with the normal liver cell line L-02, Kindlin-2 expression was increased in all six tested HCC cell lines
Summary
Kindlin-2 is a member of the focal adhesion protein family that regulates invasion and metastasis in multiple malignancies; little is known about the role of Kindlin-2 in hepatocellular carcinoma (HCC) progression. In China, hepatocellular carcinoma (HCC) is a very common cancer and the leading cause of cancer-related death. Kindlin-2, known as FERMT2 or mitogen inducible gene-2 (mig-2), is a member of the kindlin (or fermitin) family of focal adhesion proteins that regulates several physiological processes including myogenesis and myogenic differentiation [4, 5], intercalated disc formation [6, 7] and embryonic development [4, 6, 8], by enhancing integrin activation. How Kindlin-2 participates in HCC invasion and metastasis needs to be elucidated
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