Knockdown of CD44 inhibits the invasion and metastasis of hepatocellular carcinoma bothin vitroandin vivoby reversing epithelial-mesenchymal transition

// Yuan Gao 1,* , Bai Ruan 1,* , Weihui Liu 2,* , Jianlin Wang 1 , Xisheng Yang 1 , Zhuochao Zhang 1 , Xia Li 1 , Juanli Duan 1 , Fuqing Zhang 1 , Rui Ding 1 , Kaishan Tao 1 and Kefeng Dou 1 1 Department of Hepato-Biliary and Pancreto-Splenic Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, China 2 General Surgery Center of PLA, Chengdu Military General Hospital, Chengdu, China * These authors contributed equally to this work Correspondence to: Kefeng Dou, email: // Kaishan Tao, email: // Rui Ding, email: // Keywords : CD44, Hepatocellular carcinoma, epithelial-mesenchymal-transition, Snail Received : November 28, 2014 Accepted : February 02, 2015 Published : March 08, 2015 Abstract Mounting evidence has shown that induction of epithelial-mesenchymal transition (EMT) contributes to the the expression of CSC (cancer stem cell) markers. However, whether and how CSC markers could be involved in regulating EMT has rarely been reported. CD44, being one of the most commonly used CSC markers in hepatocellular carcinoma (HCC), has been demonstrated to act as a multidomain, transmembrane platform that serves to integrate a wide variety of extracellular signals. Therefore, we determined to seek whether CD44 is necessary for the EMT process in HCC. First, we noticed that CD44 expression was associated with the mesenchymal phenotype in HCC cell lines, and knocking down CD44 with lentivirus-mediated shRNA in HCC cell lines resulted in the mesenchymal-epithelial-transition (MET) and the subsequent impaired migration and invasion in vitro . Moreover, in a metastatic mice model established by tail vein injection of luciferase labelled MHCC97-H cells, we confirmed that CD44 knockdown resulted in the decreased metastasis of HCC cells. Furthermore, we found that the induction of MET by CD44 inhibition might be achieved, at least in part, by repressing the ERK/Snail pathway.