CHIP is a novel tumor suppressor in pancreatic cancer and inhibits tumor growth through targeting EGFR

// Tianxiao Wang 1 , Jingxuan Yang 2 , Jianwei Xu 1 , Jian Li 1 , Zhe Cao 1 , Li Zhou 1 , Lei You 1 , Hong Shu 1 , Zhaohui Lu 3 , Huihua Li 4 , Min Li 2 , Taiping Zhang 1 , and Yupei Zhao 1 1 Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 2 The Vivian L. Smith Department of Neurosurgery, the University of Texas Medical School at Houston, Houston, Texas, USA 3 Department of Pathology and Pathophysiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 4 Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China Correspondence: Min Li, email: // Taiping Zhang, email: // Yupei Zhao, email: // Keywords : CHIP, EGFR, pancreatic cancer, ubiquitination Received : February 25, 2014 Accepted : April 06, 2014 Published : April 08, 2014 Abstract Carboxyl terminus of heat shock protein 70-interacting protein (CHIP) is an E3 ubiquitin ligase that is involved in protein quality control and mediates several tumor-related proteins in many cancers, but the function of CHIP in pancreatic cancer is not known. Here we show that CHIP interacts and ubiquitinates epidermal growth factor receptor (EGFR) for proteasome-mediated degradation in pancreatic cancer cells, thereby inhibiting the activation of EGFR downstream pathways. CHIP suppressed cell proliferation, anchor-independent growth, invasion and migration, as well as enhanced apoptosis induced by erlotinib in vitro and in vivo . The expression of CHIP was decreased in pancreatic cancer tissues or sera. Low CHIP expression in tumor tissues was correlated with tumor differentiation and shorter overall survival. These observations indicate that CHIP serves as a novel tumor suppressor by down-regulating EGFR pathway in pancreatic cancer cells, decreased expression of CHIP was associated with poor prognosis in pancreatic cancer.