S1PR1 predicts patient survival and promotes chemotherapy drug resistance in gastric cancer cells through STAT3 constitutive activationResearch in context
Shiyu Song,
Haiyan Min,
Mengyuan Niu,
Lei Wang,
Yongzheng Wu,
Bin Zhang,
Xiufang Chen,
Qiao Liang,
Yanting Wen,
Yong Wang,
Long Yi,
Hongwei Wang,
Qian Gao
Affiliations
Shiyu Song
Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, Jiangsu Province, China
Haiyan Min
Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, Jiangsu Province, China
Mengyuan Niu
Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, Jiangsu Province, China
Lei Wang
Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, Jiangsu Province, China
Yongzheng Wu
Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, Jiangsu Province, China
Bin Zhang
Central Laboratory, Nanjing Chest Hospital, Medical School of Southeast University, Nanjing 210029, Jiangsu Province, China
Xiufang Chen
Department of Biochemistry, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China
Qiao Liang
Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, Jiangsu Province, China
Yanting Wen
Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, Jiangsu Province, China
Yong Wang
Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, Jiangsu Province, China
Long Yi
Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, Jiangsu Province, China
Hongwei Wang
Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, Jiangsu Province, China; Corresponding authors.
Qian Gao
Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, Jiangsu Province, China; Corresponding authors.
Background: S1PR1-STAT3 inter-regulatory loop was initially suggested to be oncogenic in several cancer cells. However, the clinical relevance of this mechanism in tumor progression, disease prognosis and drug response was not established. Methods: The correlations between S1PR1 transcription, overall survival and chemotherapy response of GC patients were tested using a large clinical database. The relevance of S1PR1 expression and STAT3 activation in both tumor tissues and cancer cell lines was also tested. The effect of S1PR1 high expression achieved by persistent STAT3 activation on tumor cell drug resistance was investigated in vitro and in vivo. Findings: An enhanced S1PR1 expression was highly related with a reduced overall survival time and a worse response to chemotherapy drug and closer correlation to STAT3 in gastric cancer patients. The issue chip analysis showed that the expressions of S1PR1 and STAT3 activation were increased in higher graded gastric cancer (GC) tissues. Cellular studies supported the notion that the high S1PR1 expression was responsible for drug resistance in GC cells through a molecular pattern derived by constitutive activation of STAT3. The disruption of S1PR1-STAT3 signaling significantly re-sensitized drug resistance in GC cells in vitro and in vivo. Interpretation: S1PR1-STAT3 signaling may participate drug resistance in GC, thus could serve as a drug target to increase the efficacy of GC treatment. Fund: This work was supported by the National Natural Science Foundation of China (No. 81570775, 81471095), the grant from the research projects in traditional Chinese medicine industry of China (No. 201507004-2).
