Journal Article

Sec62 promotes gastric cancer metastasis through mediating UPR-induced autophagy activation

Su, Song, Shi, Yan-Ting, Jiang, Ming-Zuo, Zhou, He, Lin, Jun-Chao, Jin, Yi-Rong, Li, Xiao-Fei, Liang, Jie, Wu, Nan, Xu, Bing, Chu, Yi

2022

Overview

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.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Adenoviridae / Adenoviruses / Adult / Aged / Aged, 80 and over / Animals / Autophagy / Autophagy - physiology / Binding / Biochemistry / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cancer / Cell adhesion & migration / Cell Biology / Cell Line, Tumor / Cell migration / cell movement / eIF-2 Kinase - genetics / Endoplasmic reticulum / Evaluation / Female / fluorescent antibody technique / Gastric cancer / Gelatinase A / Gene expression / Humans / Hydroxychloroquine - pharmacology / Immunofluorescence / Immunohistochemistry / Immunoprecipitation / Life Sciences / Male / Matrix Metalloproteinase 2 - metabolism / Membrane proteins / Membrane Transport Proteins - physiology / Metastases / Metastasis / Mice / Mice, Inbred BALB C / microarray technology / Middle Aged / Neoplasm Invasiveness / Neoplasm Metastasis / Original / Original Article / Polymerase chain reaction / precipitin tests / prognosis / Protein folding / Protein transport / Proteins / quantitative polymerase chain reaction / stomach neoplasms / Stomach Neoplasms - mortality / Stomach Neoplasms - pathology / Tissue inhibitor of metalloproteinase 1 / Tissue Inhibitor of Metalloproteinase-1 - physiology / Transmission electron microscopy / unfolded protein response / Unfolded Protein Response - physiology / Western blotting / Xenografts / Xenotransplantation