Wang Li, Chen Zhenhong, Wang Yajuan, Chang De, Su Longxiang, Guo Yinghua, Liu Changting
Tumour Biol. 2014 Jan;35(1):463-8. doi: 10.1007/s13277-013-1064-9.
The Hippo pathway plays a major role in development and organ size control, and its dysregulation contributes to tumorigenesis. WWTR1 is a transcription coactivator acting downstream of the Hippo pathway. Recently, WWTR1 has been reported to be overexpressed in several human cancers including lung cancer. However, the molecular mechanism of WWTR1 regulating lung cancer aggressiveness remains ambiguous. In the present study, we analyzed the expression of WWTR1 in NSCLC cell lines and found that WWTR1 was overexpressed at both the mRNA and protein levels. Knockdown of WWTR1 by siRNA interference in A549 cells significantly inhibited cell proliferation and increased paclitaxel-induced apoptosis. On the other side, WWTR1 overexpression in HBE cell line promoted cell proliferation and inhibited apoptosis. In addition, we found that the decreased proliferation after siRNA treatment was due to cell cycle arrest. Further analysis showed that WWTR1 could induce cyclin A, connective tissue growth factor (CTGF) expression, and inhibit caspase3 cleavage. In conclusion, WWTR1 promotes malignant cell growth and inhibits apoptosis by cyclin A and CTGF regulation.
河马通路在发育和器官大小控制中起主要作用，其失调会导致肿瘤发生。WWTR1是一种在河马通路下游起作用的转录共激活因子。最近，有报道称WWTR1在包括肺癌在内的几种人类癌症中过度表达。然而，WWTR1调节肺癌侵袭性的分子机制仍不明确。在本研究中，我们分析了非小细胞肺癌细胞系中WWTR1的表达，发现WWTR1在mRNA和蛋白质水平均过度表达。通过siRNA干扰在A549细胞中敲低WWTR1可显著抑制细胞增殖并增加紫杉醇诱导的细胞凋亡。另一方面，在HBE细胞系中过表达WWTR1可促进细胞增殖并抑制细胞凋亡。此外，我们发现siRNA处理后增殖减少是由于细胞周期停滞。进一步分析表明，WWTR1可诱导细胞周期蛋白A、结缔组织生长因子（CTGF）表达，并抑制半胱天冬酶3的切割。总之，WWTR1通过调节细胞周期蛋白A和CTGF促进恶性细胞生长并抑制细胞凋亡。
