Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital and Institute, Beijing, China.
Oncogene. 2022 Jun;41(26):3485-3497. doi: 10.1038/s41388-022-02339-1. Epub 2022 Jun 3.
We identified gamma-glutamyltransferase 7 (GGT7) to be frequently downregulated in gastric cancer, but its role remains unknown. Here we elucidated the clinical significance, functional roles, and molecular mechanism of GGT7 in gastric cancer. GGT7 was downregulated by promoter methylation and restored by demethylation treatment in gastric cancer cells. GGT7 methylation inversely correlated with mRNA expression in gastric tumors (n = 221; r = -0.686, P < 0.0001). High-expression of GGT7 in adjacent non-tumor tissues was significantly associated with favorable survival in gastric cancer patients (n = 138; P = 0.009), and was an independent prognostic factor by multivariate Cox regression (HR = 0.381, P < 0.05). GGT7 significantly inhibited gastric cancer cell growth, G1-S transition, and migration and invasion abilities. GGT7 also significantly attenuated the growth of subcutaneous xenograft tumors and reduced metastasis to the lung in nude mice. The mitophagy regulator RAB7 was identified as a direct downstream co-player of GGT7 by co-immunoprecipitation followed by mass spectrometry. Growth suppression effect of GGT7 was at least partly dependent on RAB7 by rescue experiments. GGT7 induced autophagy as shown by electron microscopy and confirmed by the increased LC3B and decreased p62. GGT7 recruited RAB7 by direct binding and drove RAB7 to translocate from nucleus to cytoplasm, subsequently mediating mitophagy by increasing mitophagy mediators/inducers. GGT7 inhibited intracellular ROS, which was associated with increased mitophagy, and subsequently suppressed MAPK signaling. Collectively, GGT7 plays a pivotal tumor-suppressing role in gastric cancer by directly binding with RAB7 to induce mitophagy and inhibit ROS and MAPK cascades. GGT7 is an independent prognostic factor for gastric cancer patients.
我们发现γ-谷氨酰转移酶 7（GGT7）在胃癌中经常下调，但它的作用尚不清楚。在这里，我们阐明了 GGT7 在胃癌中的临床意义、功能作用和分子机制。GGT7 通过启动子甲基化下调，并用去甲基化处理在胃癌细胞中恢复。GGT7 甲基化与胃癌肿瘤中的 mRNA 表达呈负相关（n=221；r=-0.686，P<0.0001）。在相邻的非肿瘤组织中高表达 GGT7 与胃癌患者的生存显著相关（n=138；P=0.009），并且是多变量 Cox 回归的独立预后因素（HR=0.381，P<0.05）。GGT7 显著抑制胃癌细胞的生长、G1-S 期过渡以及迁移和侵袭能力。GGT7 还显著减弱了裸鼠皮下异种移植肿瘤的生长并减少了向肺部的转移。通过免疫共沉淀结合质谱鉴定了 RAB7 作为 GGT7 的直接下游共同作用因子。通过挽救实验，GGT7 的生长抑制作用至少部分依赖于 RAB7。电子显微镜显示 GGT7 诱导自噬，并通过增加 LC3B 和减少 p62 得到证实。GGT7 通过直接结合招募 RAB7 并驱动 RAB7 从核内转移到细胞质，随后通过增加自噬调节剂/诱导剂来介导自噬。GGT7 抑制细胞内 ROS，这与增加自噬有关，并随后抑制 MAPK 信号通路。总之，GGT7 通过直接与 RAB7 结合诱导自噬并抑制 ROS 和 MAPK 级联，在胃癌中发挥关键的肿瘤抑制作用。GGT7 是胃癌患者的独立预后因素。
