Yuanming Pan1,2, Xin Wang1, Yuqi He1,3, Shuye Lin2,4, Min Zhu2, Yangjie Li1,3, Jianxun Wang5,6, Jiheng Wang1, Xianzong Ma1, Junfeng Xu1, Lang Yang1, Guibin Yang7, Jiaqiang Huang8,9, Youyong Lu10, Jianqiu Sheng11. 1. Department of Gastroenterology, the 7th Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing, 100700, China. 2. Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital/Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China. 3. The Second School of Clinical Medicine, Southern Medical University, 253 Middle Industrial Avenue, Guangzhou, 510282, Guangdong, China. 4. College of Life Sciences and Bioengineering, School of Science, Beijing Jiaotong University, 3 Shangyuan Residence, Haidian District, Beijing, 100044, China. 5. School of Basic Medical Sciences, Qingdao University, Qingdao, China. 6. Center for Regenerative Medicine, Institute for Translational Medicine, Qingdao University, Qingdao, China. 7. Department of Gastroenterology, Aerospace Clinic Medical College of Peking University, No. 15 Yuanquan Road, Haidian District, Beijing, 100049, China. 8. College of Life Sciences and Bioengineering, School of Science, Beijing Jiaotong University, 3 Shangyuan Residence, Haidian District, Beijing, 100044, China. jqhuang@bjtu.edu.cn. 9. Cancer and Inflammation Program (CIP), Center for Cancer Research (CCR), National Cancer Institute (NCI), Frederick, MD, USA. jqhuang@bjtu.edu.cn. 10. Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital/Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, China. youyonglu@hsc.pku.edu.cn. 11. Department of Gastroenterology, the 7th Medical Center of Chinese PLA General Hospital, No. 5 Nanmencang, Dongcheng District, Beijing, 100700, China. jianqiu@263.net.
Abstract
BACKGROUND: Hydrogen/potassium ATPase β (ATP4B) is a proton pump acting an essential role in gastric acid secretion. This study aimed to investigate the diagnostic performance of ATP4B and its biological role in tumor progression in gastric cancer. METHODS: The correlations between ATP4B expression level and clinicopathologic parameters, as well as the relevance of ATP4B expression with overall survival were assessed. The functional roles of ATP4B in gastric cancer were verified by gain- and loss-of-function cell models and tumor xenograft models. The possible downstream effects of ATP4B were analyzed by iTRAQ-based quantitative proteomics analysis. RESULTS: A dramatic decrease in ATP4B was associated with malignant transformation in gastric mucosa lesions and correlated with poor differentiation. Restoration of ATP4B expression in gastric cancer cells significantly suppressed cell proliferation, cell viability, migration, invasion, tumorigenicity and induced apoptosis, whereas ATP4B silencing exerted the opposite effects. Mechanistically, we found a quality control on mitochondrial metabolism and functions in ATP4B-overexpression GC cells. CONCLUSIONS: Our data suggest that decreasing ATP4B is an indicator for gastric mucosa malignant transformation and GC aggressive phenotype and it plays an inhibitory role in gastric cancer as a tumor suppressor via regulating mitochondrial metabolism and apoptosis pathway.
BACKGROUND: Hydrogen/potassium ATPase β (ATP4B) is a proton pump acting an essential role in gastric acid secretion. This study aimed to investigate the diagnostic performance of ATP4B and its biological role in tumor progression in gastric cancer. METHODS: The correlations between ATP4B expression level and clinicopathologic parameters, as well as the relevance of ATP4B expression with overall survival were assessed. The functional roles of ATP4B in gastric cancer were verified by gain- and loss-of-function cell models and tumor xenograft models. The possible downstream effects of ATP4B were analyzed by iTRAQ-based quantitative proteomics analysis. RESULTS: A dramatic decrease in ATP4B was associated with malignant transformation in gastric mucosa lesions and correlated with poor differentiation. Restoration of ATP4B expression in gastric cancer cells significantly suppressed cell proliferation, cell viability, migration, invasion, tumorigenicity and induced apoptosis, whereas ATP4B silencing exerted the opposite effects. Mechanistically, we found a quality control on mitochondrial metabolism and functions in ATP4B-overexpression GC cells. CONCLUSIONS: Our data suggest that decreasing ATP4B is an indicator for gastric mucosa malignant transformation and GC aggressive phenotype and it plays an inhibitory role in gastric cancer as a tumor suppressor via regulating mitochondrial metabolism and apoptosis pathway.