MiR-652 inhibits acidic microenvironment-induced epithelial-mesenchymal transition of pancreatic cancer cells by targeting ZEB1
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Shichang Deng1,2,*, Xiang Li1,*, Yi Niu1, Shuai Zhu1, Yan Jin1, Shijiang Deng1, Jingyuan Chen1, Yang Liu1,2, Chi He1, Tao Yin1, Zhiyong Yang1, Jing Tao1, Jiongxin Xiong1, Heshui Wu1, Chunyou Wang1, Gang Zhao1
1Pancreatic Disease Institute, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
2Gastrointestinal Surgery, Union Hospital West Campus, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430056, China
*These authors have contributed equally to this work
Gang Zhao, e-mail: firstname.lastname@example.org
Chunyou Wang, e-mail: email@example.com
Keywords: miR-652, ZEB1, epithelial-mesenchymal transition, acidic microenvironment, pancreatic cancer
Received: March 29, 2015 Accepted: October 06, 2015 Published: October 19, 2015
Recent evidences suggest that the acidic microenvironment might facilitate epithelial mesenchymal transition (EMT) of tumor cells, while the effects of acidity on EMT of pancreatic cancer (PC) remain undefined. The present study demonstrated that acidity suppressed miR-652 expression, which further promoted EMT process by absenting inhibition on the transcriptional factor ZEB1 expression. At first, we found that acidity remarkably enhanced invasion ability of PC cells accompanying with increased mesenchymal and decreased epithelial markers. Meanwhile, miRNAs-microarray showed that miR-652, the potential regulator of ZEB1, was distinctly decreased in acidity-treated PC cells. Furthermore, restoration of miR-652 reversed acidity-induced EMT by inhibiting ZEB1 expression, while miR-652 inhibitor induced EMT in normal PC cells through promoting ZEB1 expression. Nevertheless, knockdown of ZEB1 significantly suppressed acidity-induced EMT in PC cells, but ZEB1 overexpression rescued the EMT which was inhibited by miR-652 overexpression. The in vivo results showed that the tumor growth and liver metastasis were remarkably retarded by both miR-652 overexpression and ZEB1 knockdown. The clinical samples further revealed that miR-652 was decreased in PC tissues and antagonistically correlated with ZEB1 expression, associating with late tumor stage, lymphatic invasion and metastasis. In conclusion, our study indicated a novel acidity/miR-652/ZEB1/EMT axis in the tumorigenesis of PC.
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