Li Xiaochen, Liu Xiansheng, Xu Yongjian, Liu Jin, Xie Min, Ni Wang, Chen Shixin
Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China.
Int J Oncol. 2014 Oct;45(4):1507-14. doi: 10.3892/ijo.2014.2544. Epub 2014 Jul 17.
Transcription factor Krüppel-like factors 5 (KLF5) is overexpressed in a wide range of tumor tissues and acts as a prognostic factor in cancer. However, the role of KLF5 in non-small cell lung cancer is not clear. Hypoxia plays a vital part in the development of cancer via hypoxia-inducible factor 1 (HIF-1). Our study showed that hypoxia (1% O2) increased cell viability, clonality and proliferation and inhibited cell apoptosis in A549 cells. The expression of HIF-1α and KLF5 was increased time-dependently in hypoxia. Using small interfering RNA (siRNA) targeting KLF5 or HIF-1α, we demonstrated that KLF5 or HIF-1α knockdown inhibited hypoxia-induced cell survival and promoted cell apoptosis by actively downregulating cyclin B1, survivin and upregulating caspase-3. Given the similar effect of KLF5 and HIF-1α on cell survival, an attempt was made to investigate the putative interaction of them in hypoxia. KLF5 was revealed to co-immunoprecipitate with HIF-1α and hypoxia increased the amount of KLF5 and HIF-1α complex. Moreover, silencing of KLF5 decreased HIF-1α expression while KLF5 was not affected by HIF-1α inhibition in hypoxia, confirming the effect of KLF5 on upregulation of HIF-1α. In conclusion, this study identified hypoxia as a tumor promoter by triggering KLF5 → HIF-1α → cyclin B1/survivin/caspase-3 in lung cancer cells.
转录因子Krüppel样因子5（KLF5）在多种肿瘤组织中过表达，并在癌症中作为一个预后因素。然而，KLF5在非小细胞肺癌中的作用尚不清楚。缺氧通过缺氧诱导因子1（HIF-1）在癌症发展中起重要作用。我们的研究表明，缺氧（1% O2）可增加A549细胞的细胞活力、克隆性和增殖，并抑制细胞凋亡。在缺氧条件下，HIF-1α和KLF5的表达呈时间依赖性增加。使用靶向KLF5或HIF-1α的小干扰RNA（siRNA），我们证明，敲低KLF5或HIF-1α可通过主动下调细胞周期蛋白B1、生存素并上调半胱天冬酶-3来抑制缺氧诱导的细胞存活并促进细胞凋亡。鉴于KLF5和HIF-1α对细胞存活有相似的作用，我们试图研究它们在缺氧条件下的假定相互作用。结果显示KLF5与HIF-1α可进行共免疫沉淀，且缺氧增加了KLF5与HIF-1α复合物的量。此外，敲低KLF5可降低HIF-1α的表达，而在缺氧条件下HIF-1α的抑制并不影响KLF5，这证实了KLF5对HIF-1α上调的作用。总之，本研究通过在肺癌细胞中触发KLF5→HIF-1α→细胞周期蛋白B1/生存素/半胱天冬酶-3，确定缺氧是一种肿瘤促进因子。
