Inhibition of Snail Family Transcriptional Repressor 2 (SNAI2) Enhances Multidrug Resistance of Hepatocellular Carcinoma Cells.
Inhibition of Snail Family Transcriptional Repressor 2 (SNAI2) Enhances Multidrug Resistance of Hepatocellular Carcinoma Cells.
复制标题
抑制 Snail 家族转录阻遏蛋白 2 (SNAI2) 可增强肝细胞癌细胞的多药耐药性。
DOI：
10.1371/journal.pone.0164752
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Zhao KW
中科院分区：
文献类型：
--
作者：
Zhao XY;Li L;Wang XB;Fu RJ;Lv YP;Jin W;Meng C;Chen GQ;Huang L;Zhao KW
中国几乎占全球肝癌病例和死亡总数的一半，而肝细胞癌是最主要的肝癌。Snail家族转录抑制因子2(SNAI2)是一种上皮细胞向间充质细胞转化的转录因子，可驱动肿瘤上皮细胞向间充质细胞转化。然而，内源性SNAI2在不同类型的恶性肿瘤中的作用仍存在争议。在这里，我们惊讶地发现，当SNAI2的表达被shRNAs抑制时，肝癌细胞的锚定非依赖性生长，包括肿瘤球体和软琼脂集落的形成，显著增加。抑制SNAI2足以上调几个癌症干细胞基因。尽管与转移能力无关，但抑制SNAI2确实增加了Hoechst 33342的外排，并增强了体内外的多药耐药性。与此数据一致，我们首次证明了降低SNAI2水平可以在转录上上调几个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以挽救SNAI2抑制引起的多药耐药。我们的结果表明，SNAI2通过抑制肝癌细胞中的ABC转运蛋白基因来抑制多药耐药，从而发挥肿瘤抑制作用。
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.
登录
查看更多内容
影响因子：
11.8
作者：
Langer, Ellen M.;Feng, Yunfeng;Longmore, Gregory D.
通讯作者：
Longmore, Gregory D.
影响因子：
3.8
作者：
Haslehurst AM;Koti M;Dharsee M;Nuin P;Evans K;Geraci J;Childs T;Chen J;Li J;Weberpals J;Davey S;Squire J;Park PC;Feilotter H
通讯作者：
Feilotter H
影响因子：
2.7
作者：
Jiang, RL;Lan, Y;Gridley, T
通讯作者：
Gridley, T
影响因子：
3.5
作者：
Antonio Perez-Mancera, Pedro;Bermejo-Rodriguez, Camino;Sanchez-Garcia, Isidro
通讯作者：
Sanchez-Garcia, Isidro
影响因子：
4
作者：
Bolós, V;Peinado, H;Cano, A
通讯作者：
Cano, A