title: Inhibition of Snail Family Transcriptional Repressor 2 (SNAI2) Enhances Multidrug Resistance of Hepatocellular Carcinoma Cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Wang
authors.affiliation: Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTU-SM, Shanghai, China.
authors.forename: Rong-Jie
authors.initials: RJ
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Lv
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.affiliation: Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Meng
authors.affiliation: 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.
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Ke-Wen
authors.identifier: http://orcid.org/0000-0003-3135-1607
authors.initials: KW
authors.lastname: Zhao
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D000071250:Snail Family Transcription Factors / Q000172:deficiency* / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D014700:Verapamil / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D034741:RNA, Small Interfering; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; D014700:Verapamil