Jianwu Jiang1,2,3,4, Wei Chang5, Yang Fu1, Yongshun Gao1, Chunlin Zhao1, Xiefu Zhang1, Shuijun Zhang2,3,4,6. 1. Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 2. Department of Henan Key Laboratory of Digestive Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. 3. Department of Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. 4. Department of ZhengZhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. 5. Department of Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. 6. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Abstract
OBJECTIVES: SAV1 is a human homologue of Salvador that contains two protein-protein interaction modules known as WW domains and acts as a scaffolding protein. SAV1 participates in the development of diverse types of cancer. We aimed to investigate the role of SAV1 in human colorectal cancer. MATERIALS AND METHODS: Human colorectal cancer samples were used to study the expression of SAV1 and YAP. Loss-of-function and gain-of-function strategies were used to study the effects of SAV1 on colorectal cancer cell growth. Rapamycin was used to treat cells and mice to investigate the effect of mTOR signalling. RESULTS: SAV1 represses the development of colorectal cancer by inhibiting the Akt-mTOR signalling in a YAP-dependent manner. The mRNA and protein levels of SAV1 are down-regulated in human colorectal cancer tissues compared with adjacent non-cancer tissues. SAV1 knockdown promotes the growth of colorectal cancer cells in vitro and in vivo, whereas SAV1 overexpression leads to opposing results. SAV1 represses the activation of the Akt-mTOR signalling, and rapamycin treatment blunts the effects of SAV1 on in vitro and in vivo growth of colorectal cancer cells. Finally, we show that SAV1 promotes the phosphorylation and inactivation of YAP, which contributes to the effect of SAV1 on Akt-mTOR signalling pathway. CONCLUSIONS: SAV1 is a repressor during the development of human colorectal cancer by inhibiting the YAP-Akt-mTOR signalling pathway.
OBJECTIVES:SAV1 is a human homologue of Salvador that contains two protein-protein interaction modules known as WW domains and acts as a scaffolding protein. SAV1 participates in the development of diverse types of cancer. We aimed to investigate the role of SAV1 in humancolorectal cancer. MATERIALS AND METHODS:Humancolorectal cancer samples were used to study the expression of SAV1 and YAP. Loss-of-function and gain-of-function strategies were used to study the effects of SAV1 on colorectal cancer cell growth. Rapamycin was used to treat cells and mice to investigate the effect of mTOR signalling. RESULTS:SAV1 represses the development of colorectal cancer by inhibiting the Akt-mTOR signalling in a YAP-dependent manner. The mRNA and protein levels of SAV1 are down-regulated in humancolorectal cancer tissues compared with adjacent non-cancer tissues. SAV1 knockdown promotes the growth of colorectal cancer cells in vitro and in vivo, whereas SAV1 overexpression leads to opposing results. SAV1 represses the activation of the Akt-mTOR signalling, and rapamycin treatment blunts the effects of SAV1 on in vitro and in vivo growth of colorectal cancer cells. Finally, we show that SAV1 promotes the phosphorylation and inactivation of YAP, which contributes to the effect of SAV1 on Akt-mTOR signalling pathway. CONCLUSIONS:SAV1 is a repressor during the development of humancolorectal cancer by inhibiting the YAP-Akt-mTOR signalling pathway.
Authors: Tyler M Foley; Susan N Payne; Cheri A Pasch; Alex E Yueh; Dana R Van De Hey; Demetra P Korkos; Linda Clipson; Molly E Maher; Kristina A Matkowskyj; Michael A Newton; Dustin A Deming Journal: Mol Cancer Res Date: 2017-02-09 Impact factor: 5.852
Authors: Bo Hwa Sohn; Jae-Jun Shim; Sang-Bae Kim; Kyu Yun Jang; Soo Mi Kim; Ji Hoon Kim; Jun Eul Hwang; Hee-Jin Jang; Hyun-Sung Lee; Sang-Cheol Kim; Woojin Jeong; Sung Soo Kim; Eun Sung Park; Jeonghoon Heo; Yoon Jun Kim; Dae-Ghon Kim; Sun-Hee Leem; Ahmed Kaseb; Manal M Hassan; Minse Cha; In-Sun Chu; Randy L Johnson; Yun-Yong Park; Ju-Seog Lee Journal: Clin Cancer Res Date: 2015-10-12 Impact factor: 12.531
Authors: Alex Bainbridge; Scott Walker; Joseph Smith; Kathryn Patterson; Aparna Dutt; Yi Min Ng; Huw D Thomas; Laura Wilson; Benjamin McCullough; Dominic Jones; Arussa Maan; Peter Banks; Stuart R McCracken; Luke Gaughan; Craig N Robson; Kelly Coffey Journal: Nucleic Acids Res Date: 2020-06-04 Impact factor: 16.971