Inhibition of Snail Family Transcriptional Repressor 2 (SNAI2) Enhances Multidrug Resistance of Hepatocellular Carcinoma Cells

PLoS One. 2016 Oct 19;11(10):e0164752. doi: 10.1371/journal.pone.0164752. eCollection 2016.

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.

MeSH terms

  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / genetics
  • Animals
  • Carcinoma, Hepatocellular / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Drug Resistance, Multiple / drug effects
  • Drug Resistance, Multiple / genetics*
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Silencing
  • Humans
  • Liver Neoplasms / pathology*
  • Mice
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • RNA, Small Interfering / genetics
  • Snail Family Transcription Factors / deficiency*
  • Snail Family Transcription Factors / genetics*
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / genetics
  • Up-Regulation / drug effects
  • Up-Regulation / genetics
  • Verapamil / pharmacology

Substances

  • ATP-Binding Cassette Transporters
  • RNA, Small Interfering
  • SNAI2 protein, human
  • Snail Family Transcription Factors
  • Verapamil

Grants and funding

This work was supported by grant 2012CB967003 (to L. Huang) from National Basic Research Program of China (973 Program) (<http://www.most.gov.cn);/> http://www.most.gov.cn); grant 81171888 and 81572692 (to KW Zhao) and 81272262 (to L Huang) from National Science Foundation of China (<http://www.nsfc.gov.cn/);> http://www.nsfc.gov.cn/); ‘Pu Jiang’ project 14PJ1406300 (to C. Meng) from Shanghai Science and Technology Committee (<http://www.stcsm.gov.cn/).> http://www.stcsm.gov.cn/).