Dan Dong1, Lei Na1,2, Kailing Zhou1, Zhuo Wang1, Yu Sun1, Qianqian Zheng1, Jian Gao3, Chenghai Zhao4, Wei Wang5. 1. Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, People's Republic of China. 2. Department of Urology, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China. 3. Center of Laboratory Technology and Experimental Medicine, China Medical University, Shenyang, People's Republic of China. 4. Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, People's Republic of China. chzhao@cmu.edu.cn. 5. Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, People's Republic of China. wangwei07@cmu.edu.cn.
Abstract
BACKGROUND: Frizzled (FZD) proteins function as receptors for WNT ligands. Members in FZD family including FZD2, FZD4, FZD7, FZD8 and FZD10 have been demonstrated to mediate cancer cell epithelial-mesenchymal transition (EMT). METHODS: CCLE and TCGA databases were interrogated to reveal the association of FZD5 with EMT. EMT was analyzed by investigating the alterations in CDH1 (E-cadherin), VIM (Vimentin) and ZEB1 expression, cell migration and cell morphology. Transcriptional modulation was determined by ChIP in combination with Real-time PCR. Survival was analyzed by Kaplan-Meier method. RESULTS: In contrast to other FZDs, FZD5 was identified to prevent EMT in gastric cancer. FZD5 maintains epithelial-like phenotype and is negatively modulated by transcription factors SNAI2 and TEAD1. Epithelial-specific factor ELF3 is a downstream effecter, and protein kinase C (PKC) links FZD5 to ELF3. ELF3 represses ZEB1 expression, further guarding against EMT. Moreover, FZD5 signaling requires its co-receptor LRP5 and WNT7B is a putative ligand for FZD5. FZD5 and ELF3 are associated with longer survival, whereas SNAI2 and TEAD1 are associated with shorter survival. CONCLUSIONS: Taken together, FZD5-ELF3 signaling blocks EMT, and plays a potential tumor-suppressing role in gastric cancer. Video Abstract.
BACKGROUND: Frizzled (FZD) proteins function as receptors for WNT ligands. Members in FZD family including FZD2, FZD4, FZD7, FZD8 and FZD10 have been demonstrated to mediate cancer cell epithelial-mesenchymal transition (EMT). METHODS: CCLE and TCGA databases were interrogated to reveal the association of FZD5 with EMT. EMT was analyzed by investigating the alterations in CDH1 (E-cadherin), VIM (Vimentin) and ZEB1 expression, cell migration and cell morphology. Transcriptional modulation was determined by ChIP in combination with Real-time PCR. Survival was analyzed by Kaplan-Meier method. RESULTS: In contrast to other FZDs, FZD5 was identified to prevent EMT in gastric cancer. FZD5 maintains epithelial-like phenotype and is negatively modulated by transcription factors SNAI2 and TEAD1. Epithelial-specific factor ELF3 is a downstream effecter, and protein kinase C (PKC) links FZD5 to ELF3. ELF3 represses ZEB1 expression, further guarding against EMT. Moreover, FZD5 signaling requires its co-receptor LRP5 and WNT7B is a putative ligand for FZD5. FZD5 and ELF3 are associated with longer survival, whereas SNAI2 and TEAD1 are associated with shorter survival. CONCLUSIONS: Taken together, FZD5-ELF3 signaling blocks EMT, and plays a potential tumor-suppressing role in gastric cancer. Video Abstract.
Entities:
Keywords:
ELF3; Epithelial-mesenchymal transition; FZD5; Gastric cancer
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