Identification of Glypican-3 as a potential metastasis suppressor gene in gastric cancer

// Shiwei Han 1, 2, 3, * , Xuemei Ma 1, 3, * , Yanxia Zhao 4, * , Hongying Zhao 5 , Ana Batista 2 , Sheng Zhou 6 , Xiaona Zhou 1, 3 , Yao Yang 1, 3 , Tingting Wang 1, 3 , Jingtao Bi 7 , Zheng Xia 8 , Zhigang Bai 1, 3 , Igor Garkavtsev 2 , Zhongtao Zhang 1, 3 1 Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China 2 Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA 3 Beijing Key Laboratory of Cancer Invasion and Metastasis Research & National Clinical Research Center for Digestive Diseases, Beijing, China 4 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 5 Department of Pathology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China 6 Institute of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 7 Department of General Surgery, Beijing Jishuitan Hospital, The Fourth Medical College of Peking University, Beijing, China 8 Department of Surgery, Xiangya Hospital, Central South University, Changsha, China * These authors have contributed equally to this work Correspondence to: Shiwei Han, email: shiwei@steele.mgh.harvard.edu Zhongtao Zhang, email: zhangzht@medmail.com.cn Keywords: gastric cancer, Glypican-3, metastasis, FoxM1, Erk1/2 Received: July 02, 2015      Accepted: May 23, 2016      Published: June 01, 2016 ABSTRACT Gastric cancer is a prevalent tumor that is usually detected at an advanced metastatic stage. Currently, standard therapies are mostly ineffective. Here, we report that Glypican-3 (GPC3) is absent in invasive tumors and metastatic lymph nodes, in particular in aggressive and highly disseminated signet ring cell carcinomas. We demonstrate that loss of GPC3 correlates with poor overall survival in patients. Moreover, we show that absence of GPC3 causes up-regulation of MAPK/FoxM1 signaling and that blockade of this pathway alters cellular invasion. An inverse correlation between GPC3 and FoxM1 is also shown in patient samples. These data identify GPC3 as a potential metastasis suppressor gene and suggest its value as a prognostic marker in gastric cancer. Development of therapies targeting signaling downstream of GPC3 are warranted.