Oncotarget

Research Papers:

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 _, Xiao-Lin Lin, Hui-Yan Wang, Yu-Juan Qin, Lin Chen, Jing Li, Jun-Shuang Jia, Hong-Fen Shen, Sheng Yang, Rao-Ying Xie, Fang Wei, Fei Gao, Xiao-Xiang Rong, Jie Yang, Wen-Tao Zhao, Ting-Ting Zhang, Jun-Wen Shi, Kai-Tai Yao, Wei-Ren Luo, Yan Sun and Dong Xiao

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Oncotarget. 2015; 6:36713-36730. https://doi.org/10.18632/oncotarget.5457

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Abstract

Sheng-Chun Wang1,4,*, Xiao-Lin Lin1,*, Hui-Yan Wang1,*, Yu-Juan Qin1, Lin Chen1, Jing Li1, Jun-Shuang Jia1, Hong-Fen Shen1, Sheng Yang1, Rao-Ying Xie1, Fang Wei1, Fei Gao1,6, Xiao-Xiang Rong5, Jie Yang1, Wen-Tao Zhao1, Ting-Ting Zhang1, Jun-Wen Shi1, Kai-Tai Yao1, Wei-Ren Luo1, Yan Sun3, Dong Xiao1,2

1Cancer Research Institute, Southern Medical University, Guangzhou 510515, China

2Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou 510515, China

3Joint Program in Transfusion Medicine, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA

4Department of Pathology, Guangdong Medical University, Dongguan 523808, China

5Department of Oncology, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong 510315, China

6Department 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.


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