798 GAMMA-GLUTAMYLTRANSFERASE 7 SUPPRESSES GASTRIC CARCINOGENESIS BY COOPERATING WITH RAB7 TO MEDIATE MITOPHAGY

Background and Aims By integrative genomics analysis, we identified gamma-glutamyltransferase 7 (GGT7) to be frequently downregulated by promoter hypermethylation in gastric cancer. However, the role of GGT7 is largely unknown. This study elucidated the functional roles, molecular mechanism and clinical significance of GGT7 in gastric carcinogenesis. Methods The biological function of GGT7 was studied in vitro and in vivo. Downstream effectors and pathways were elucidated by co-immunoprecipitation (co-IP) followed by mass spectrometry and RNA-sequencing. Results GGT7 expression was frequently downregulated by promoter methylation as shown by bisulfite genomic sequencing in gastric cancer cells, which could be restored by demethylation treatment. GGT7 methylation was inversely correlated with its mRNA expression in primary gastric tumors of TCGA cohort (n=221, r=-0.686, P Conclusions GGT7 plays a pivotal tumor-suppressing role in gastric carcinogenesis by direct binding with RAB7 to further induce mitophagy and inhibit ROS and MAPK cascades. GGT7 expression in adjacent non-tumor tissues serves as an independent prognostic factor for gastric cancer patients.