Department of Pathology, The School of Basic Medical Sciences, Fujian Medical University, No.1, Xuefu North Road, University Town, Fuzhou, 350122, Fujian, China.
Department of Pathology, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China.
J Exp Clin Cancer Res. 2017 Sep 29;36(1):134. doi: 10.1186/s13046-017-0603-4.
Kindlin-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.
Immunohistochemistry 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.
High 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.
Kindlin-2 promotes HCC invasion, metastasis and epithelial-mesenchymal transition through Wnt/β-catenin signaling.
Kindlin-2 是黏着斑蛋白家族的一员，可调节多种恶性肿瘤的侵袭和转移；然而，关于 Kindlin-2 在肝细胞癌（HCC）进展中的作用知之甚少。
采用免疫组织化学法检测 177 对人 HCC 及其相邻肝组织样本中 Kindlin-2 的表达。在 MHCC97H、LM3 和 SMMC7721 细胞中评估 Kindlin-2 对 HCC 细胞系体外侵袭和迁移的作用。应用微阵列表达分析探讨 Kindlin-2 促进 HCC 进展的分子机制。采用定量实时 PCR 和 Western blot 验证微阵列结果。
高表达 Kindlin-2 与侵袭性 HCC 的临床病理特征显著相关，包括肿瘤包膜、微血管侵犯、肝外转移和预后不良。体外，Kindlin-2 敲除或敲低抑制 HCC 细胞黏附、迁移和侵袭，而外源性 Kindlin-2 表达促进这些过程。重要的是，Kindlin-2 激活了 Wnt/β-catenin 信号通路并增加了 β-catenin 的表达，特别是非磷酸化 β-catenin 的水平，以及 Wnt/β-catenin 信号通路的两个靶标 Axin2 和 MMP7。Kindlin-2 还诱导了 HCC 细胞表达谱的改变，表明细胞发生上皮间质转化。例如，上皮标志物 E-钙黏蛋白的表达下调，而间充质标志物波形蛋白、N-钙黏蛋白和 Snail 的表达上调。
Kindlin-2 通过 Wnt/β-catenin 信号通路促进 HCC 的侵袭、转移和上皮间质转化。
