Song Su1,2, Yan-Ting Shi1, Yi Chu1, Ming-Zuo Jiang1, Nan Wu3, Bing Xu4, He Zhou1, Jun-Chao Lin1, Yi-Rong Jin1, Xiao-Fei Li1, Jie Liang5. 1. State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University (Air Force Medical University), Changle West Road 127, Xi'an, Shaanxi, 710032, China. 2. The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100071, China. 3. College of Life Sciences, Northwest University, Xi'an, Shaanxi, 710069, China. 4. Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. School of Medicine, Northwest University, 229 Taibai North Road, Xi'an, Shaanxi, 710069, China. 5. State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University (Air Force Medical University), Changle West Road 127, Xi'an, Shaanxi, 710032, China. liangjie@fmmu.edu.cn.
Abstract
BACKGROUND AND AIMS: Sec62 is a membrane protein of the endoplasmic reticulum that facilitates protein transport. Its role in cancer is increasingly recognised, but remains largely unknown. We investigated the functional role of Sec62 in gastric cancer (GC) and its underlying mechanism. METHODS: Bioinformatics, tissue microarray, immunohistochemistry (IHC), western blotting (WB), quantitative polymerase chain reaction (qPCR), and immunofluorescence were used to examine the expression of target genes. Transwell, scratch healing assays, and xenograft models were used to evaluate cell migration and invasion. Transmission electron microscopy and mRFP-GFP-LC3 double-labeled adenoviruses were used to monitor autophagy. Co-immunoprecipitation (CO-IP) was performed to evaluate the binding activity between the proteins. RESULTS: Sec62 expression was upregulated in GC, and Sec62 upregulation was an independent predictor of poor prognosis. Sec62 overexpression promoted GC cell migration and invasion both in vitro and in vivo. Sec62 promoted migration and invasion by affecting TIMP-1 and MMP2/9 balance. Moreover, Sec62 could activate autophagy by upregulating PERK/ATF4 expression and binding to LC3II with concomitant FIP200/Beclin-1/Atg5 activation. Furthermore, autophagy blockage impaired the promotive effects of Sec62 on GC cell migration and invasion, whereas autophagy activation rescued the inhibitory effect of Sec62 knockdown on GC metastasis. Notably, Sec62 inhibition combined with autophagy blockage exerted a synergetic anti-metastatic effect in vitro and in vivo. CONCLUSION: Sec62 promotes GC metastasis by activating autophagy and subsequently regulating TIMP-1 and MMP2/9 balance. The activation of autophagy by Sec62 may involve the unfolded protein response (UPR)-related PERK/ATF4 pathway and binding of LC3II during UPR recovery involving FIP200/Beclin-1/Atg5 upregulation. Specifically, the dual inhibition of Sec62 and autophagy may provide a promising therapeutic strategy for GC metastasis.
BACKGROUND AND AIMS: Sec62 is a membrane protein of the endoplasmic reticulum that facilitates protein transport. Its role in cancer is increasingly recognised, but remains largely unknown. We investigated the functional role of Sec62 in gastric cancer (GC) and its underlying mechanism. METHODS: Bioinformatics, tissue microarray, immunohistochemistry (IHC), western blotting (WB), quantitative polymerase chain reaction (qPCR), and immunofluorescence were used to examine the expression of target genes. Transwell, scratch healing assays, and xenograft models were used to evaluate cell migration and invasion. Transmission electron microscopy and mRFP-GFP-LC3 double-labeled adenoviruses were used to monitor autophagy. Co-immunoprecipitation (CO-IP) was performed to evaluate the binding activity between the proteins. RESULTS: Sec62 expression was upregulated in GC, and Sec62 upregulation was an independent predictor of poor prognosis. Sec62 overexpression promoted GC cell migration and invasion both in vitro and in vivo. Sec62 promoted migration and invasion by affecting TIMP-1 and MMP2/9 balance. Moreover, Sec62 could activate autophagy by upregulating PERK/ATF4 expression and binding to LC3II with concomitant FIP200/Beclin-1/Atg5 activation. Furthermore, autophagy blockage impaired the promotive effects of Sec62 on GC cell migration and invasion, whereas autophagy activation rescued the inhibitory effect of Sec62 knockdown on GC metastasis. Notably, Sec62 inhibition combined with autophagy blockage exerted a synergetic anti-metastatic effect in vitro and in vivo. CONCLUSION: Sec62 promotes GC metastasis by activating autophagy and subsequently regulating TIMP-1 and MMP2/9 balance. The activation of autophagy by Sec62 may involve the unfolded protein response (UPR)-related PERK/ATF4 pathway and binding of LC3II during UPR recovery involving FIP200/Beclin-1/Atg5 upregulation. Specifically, the dual inhibition of Sec62 and autophagy may provide a promising therapeutic strategy for GC metastasis.
Authors: Maximilian Linxweiler; Johannes Linxweiler; Monika Barth; Julia Benedix; Volker Jung; Yoo-Jin Kim; Rainer M Bohle; Richard Zimmermann; Markus Greiner Journal: Am J Pathol Date: 2011-12-21 Impact factor: 4.307
Authors: Maximilian Linxweiler; Florian Bochen; Bernhard Schick; Silke Wemmert; Basel Al Kadah; Markus Greiner; Andrea Hasenfus; Rainer-Maria Bohle; Ingolf Juhasz-Böss; Erich-Franz Solomayer; Zoltan Ferenc Takacs Journal: BMC Cancer Date: 2016-08-23 Impact factor: 4.430
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