Guo Chao, Wang Xintian, Liang Lufeng
Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital Changsha 410005, P.R. China.
Int J Clin Exp Pathol. 2015 Feb 1;8(2):1690-7. eCollection 2015.
YAP (yes-associated protein) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes, including proliferation and apoptosis. Although YAP plays an important role in various tumors, the underlying mechanism in hepatocellular carcinoma (HCC) tumorigenesis remains unclear. In this study, we observed that the LATS2 was highly expressed in Bel-7402 and HepG2 cell lines, and LATS2 protein level was negatively correlated with YAP1 in HCC cells. And then, we inhibited LATS2 expression by transfecting with siRNA. Western blot and Immunofluorescent staining analysis demonstrated that LATS2 inhibition decreased the dephosphorylation of YAP1 protein and promoted YAP1 nuclear accumulation in HCC cells. Moreover, Immunoprecipitation assay results also indicated that Yap binds directly to TEAD2 and LATS2 inhibition-mediated dephosphorylation increased the YAP1/TEAD2 association, leading to YAP1/TEAD2 transcriptional activation, which in turn upregulated cell invasion in HCC cells. Taken together, our current data indicated a new regulatory mechanism of YAP1 by the LATS2-mediated phosphorylation that was involved in HCC tumorigenesis.
YAP（Yes相关蛋白）是一种转录共激活因子，作用于Hippo信号通路下游，调节包括增殖和凋亡在内的多种细胞过程。尽管YAP在各种肿瘤中发挥重要作用，但其在肝细胞癌（HCC）肿瘤发生中的潜在机制仍不清楚。在本研究中，我们观察到LATS2在Bel-7402和HepG2细胞系中高表达，且在HCC细胞中LATS2蛋白水平与YAP1呈负相关。然后，我们通过转染siRNA抑制LATS2表达。蛋白质免疫印迹和免疫荧光染色分析表明，抑制LATS2可降低HCC细胞中YAP1蛋白的去磷酸化并促进YAP1核内积累。此外，免疫沉淀试验结果还表明，Yap直接与TEAD2结合，抑制LATS2介导的去磷酸化增加了YAP1/TEAD2的结合，导致YAP1/TEAD2转录激活，进而上调HCC细胞的侵袭能力。综上所述，我们目前的数据表明LATS2介导的磷酸化对YAP1具有一种新的调控机制，该机制参与了HCC的肿瘤发生。
