Zhao Xin-Yu, Li Lei, Wang Xiao-Bo, Fu Rong-Jie, Lv Ya-Ping, Jin Wei, Meng Chao, Chen Guo-Qiang, Huang Lei, Zhao Ke-Wen
Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education of China, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTU-SM, Shanghai, China.
PLoS One. 2016 Oct 19;11(10):e0164752. doi: 10.1371/journal.pone.0164752. eCollection 2016.
China accounts for almost half of the total number of liver cancer cases and deaths worldwide, and hepatocellular carcinoma (HCC) is the most primary liver cancer. Snail family transcriptional repressor 2 (SNAI2) is known as an epithelial to mesenchymal transition-inducing transcription factor that drives neoplastic epithelial cells into mesenchymal phenotype. However, the roles of endogenous SNAI2 remain controversial in different types of malignant tumors. Herein, we surprisingly identify that anchorage-independent growth, including the formation of tumor sphere and soft agar colony, is significantly increased when SNAI2 expression is inhibited by shRNAs in HCC cells. Suppression of SNAI2 suffices to up-regulate several cancer stem genes. Although unrelated to the metastatic ability, SNAI2 inhibition does increase the efflux of Hoechst 33342 and enhance multidrug resistance in vitro and in vivo. In agreement with this data, we demonstrate for the first time that decreasing SNAI2 level can transcriptionally upregulate several ATP binding cassette (ABC) transporter genes such as ABCB1. Moreover, ABC transporters' inhibitor verapamil can rescue the multidrug resistance induced by SNAI2 inhibition. Our results implicate that SNAI2 behaves as a tumor suppressor by inhibiting multidrug resistance via suppressing ABC transporter genes in HCC cells.
中国的肝癌病例和死亡总数几乎占全球的一半，而肝细胞癌（HCC）是最主要的原发性肝癌。蜗牛家族转录抑制因子2（SNAI2）是一种上皮-间质转化诱导转录因子，可促使肿瘤上皮细胞转变为间质表型。然而，内源性SNAI2在不同类型恶性肿瘤中的作用仍存在争议。在此，我们惊人地发现，当通过短发夹RNA（shRNAs）抑制HCC细胞中的SNAI2表达时，包括肿瘤球形成和软琼脂集落形成在内的非锚定依赖性生长显著增加。抑制SNAI2足以上调多个癌症干细胞基因。虽然与转移能力无关，但抑制SNAI2确实会增加Hoechst 33342的外排，并在体外和体内增强多药耐药性。与此数据一致，我们首次证明降低SNAI2水平可转录上调多个ATP结合盒（ABC）转运蛋白基因，如ABCB1。此外，ABC转运蛋白抑制剂维拉帕米可挽救由SNAI2抑制诱导的多药耐药性。我们的结果表明，SNAI2在HCC细胞中通过抑制ABC转运蛋白基因来抑制多药耐药性，从而发挥肿瘤抑制作用。
