Hes1 triggers epithelial-mesenchymal transition (EMT)-like cellular marker alterations and promotes invasion and metastasis of nasopharyngeal carcinoma by activating the PTEN/AKT pathway

// Sheng-Chun Wang 1, 4, * , Xiao-Lin Lin 1, * , Hui-Yan Wang 1, * , Yu-Juan Qin 1 , Lin Chen 1 , Jing Li 1 , Jun-Shuang Jia 1 , Hong-Fen Shen 1 , Sheng Yang 1 , Rao-Ying Xie 1 , Fang Wei 1 , Fei Gao 1, 6 , Xiao-Xiang Rong 5 , Jie Yang 1 , Wen-Tao Zhao 1 , Ting-Ting Zhang 1 , Jun-Wen Shi 1 , Kai-Tai Yao 1 , Wei-Ren Luo 1 , Yan Sun 3 , Dong Xiao 1, 2 1 Cancer Research Institute, Southern Medical University, Guangzhou 510515, China 2 Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China 3 Joint Program in Transfusion Medicine, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA 4 Department of Pathology, Guangdong Medical University, Dongguan 523808, China 5 Department of Oncology, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong 510315, China 6 Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China * These authors have contributed equally to this work Correspondence to: Dong Xiao, e-mail: Xiao_d@hotmail.com Yan Sun, e-mail: suny528@gmail.com Wei-Ren Luo, e-mail: luoweiren@hotmail.com Keywords: Hes1, nasopharyngeal carcinoma (NPC), epithelial-mesenchymal transition (EMT), cancer invasion and metastasis, PTEN Received: December 16, 2014      Accepted: September 21, 2015      Published: October 02, 2015 ABSTRACT Overexpression of the transcriptional factor Hes1 (hairy and enhancer of split-1) has been observed in numerous cancers, but the precise roles of Hes1 in epithelial-mesenchymal transition (EMT), cancer invasion and metastasis remain unknown. Our current study firstly revealed that Hes1 upregulation in a cohort of human nasopharyngeal carcinoma (NPC) biopsies is significantly associated with the EMT, invasive and metastatic phenotypes of cancer. In the present study, we found that Hes1 overexpression triggered EMT-like cellular marker alterations of NPC cells, whereas knockdown of Hes1 through shRNA reversed the EMT-like phenotypes, as strongly supported by Hes1-mediated EMT in NPC clinical specimens described above. Gain-of-function and loss-of-function experiments demonstrated that Hes1 promoted the migration and invasion of NPC cells in vitro . In addition, exogenous expression of Hes1 significantly enhanced the metastatic ability of NPC cells in vivo . Chromatin immunoprecipitation (ChIP) assays showed that Hes1 inhibited PTEN expression in NPC cells through binding to PTEN promoter region. Increased Hes1 expression and decreased PTEN expression were also observed in a cohort of NPC biopsies. Additional studies demonstrated that Hes1-induced EMT-like molecular changes and increased motility and invasion of NPC cells were mediated by PTEN. Taken together, our results suggest, for what we believe is the first time, that Hes1 plays an important role in the invasion and metastasis of NPC through inhibiting PTEN expression to trigger EMT-like phenotypes.