FAT1 prevents epithelial mesenchymal transition (EMT) via MAPK/ERK signaling pathway in esophageal squamous cell cancer
Authors: Caixia Cheng
Ruyi Shi
Xiaoling Hu
Yingchun Zhang
Yongping Cui
Ling Zhang
Mingsheng Zhang
Jing Liu
Lu Chang
Yanghui Bi
Juan Wang
Hongyi Li
Zhiwu Jia
Jie Yang
Yuanfang Zhai
Yaoping Li
Yu Qian
Jian Yang
Enwei Xu
Guodong Li
Yanchun Ma
Pengzhou Kong
Xiaolong Cheng
Ting Yan
Bin Song
Heyang Cui
Yi Wang
Fang Wang
Bin Yang
Journal: Cancer Letters (2017)
Discipline: CLINICAL MEDICINE
Keywords: EMT; ESCC; FAT1; MAPK pathway; Tumor suppressor.
Affiliations: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China., Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Department of Anatomy, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China., Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China., Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Department of Pathology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China., Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Department of Anorectum, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030001, PR China., Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Department of General Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, PR China., Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, PR China., Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Department of Oncology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China., Department of Otorhinolaryngology, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030001, PR China., Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Department of General Surgery, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China., Department of Pharmacology, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China., Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, PR China. Electronic address: .

Abstract:  FAT1 regulates cell-cell adhesion, cell growth, cell migration, and actin dynamics as either oncogene or tumor suppressor in human cancers. We previously identified FAT1 was one of significant mutant genes in esophageal squamous cell carcinoma (ESCC). However, the function and underlying mechanism of FAT1 in ESCC have not been explored. In this study, we report that FAT1 expression was significantly lower in ESCC tumor tissues. Exogenous expression of FAT1 led to inhibition of cell proliferation and colony formation, as well as cell migration and invasion whereas FAT1 knockdown showed the opponent trends in vitro and in vivo. Moreover, FAT1 knockdown led to a statistically decrease of E-cadherin expression and a dramatically increase expression of N-cadherin, Vimentin, and Snail in a MAPK/ERK pathway-dependent manner. Meanwhile, over-expression of FAT1 resulted in the opposite trends. These alterations were abrogated in the presence of U0126, a MEK specific inhibitor. Collectively, our studies identified a novel role for FAT1 in inhibiting tumor growth and EMT occurrence in ESCC. We proposed that disruption of MAPK/ERK pathway by FAT1 contributes the EMT in ESCC and has important implications for understanding ESCC development. 

Retracted: No

PubPeer comments:
 Figure 3 A and C use images twice for different cell lines and treatments.   Additionally, the bottom left 3 images in 3A are extremely poor quality and the background is a different color. , 
 We thank Dr. Dendrodoa Grossularia so much for pointing out the mistake in Figure 3A and C. We do deepest apologize to all readers for the mistake we made. We mistakely sortied the imges of 109NC and 109FAT1WT. We have checked the original data and corrected the mistake. Please check the corrected figure. We are contacting the editor office of Cancer Letter to make correction of this figure. Thank you again. We are really appreciated for your comment.  , 
  An obvious splice in Fig. 6B, p-ERK1 2, could the authors explain? , 
 #3 We thank very much for your comment. In the experiment, we run different gel of 150NC, FAT1sh1, FAT1sh2 in the absence or presence of U0126 to block p-ERK1 2, total ERK1 2, and other proteins. We run the gels for western blotting following the loading sequence: 150NC, FAT1sh1, FAT1sh2 in the absence of U0126, and then following 150NC, FAT1sh1, FAT1sh2 in the presence of U0126. However, we accidently loaded the samples of 150NC, FAT1sh1, FAT1sh2 with U0126 firstly and then samples without U0126 for blocking p-ERK1 2 (see the following initial photo). To easily compare the protein levels, we cut the p-ERK1 2 blot of 150NC, FAT1sh1, FAT1sh2 with U0126, and switched them after150NC, FAT1sh1, FAT1sh2 without U0126. The initial photo of western blot for p-ERK1 2 of KYSE150 as following.  ,