Yang Suzhen, Zhang Jing, Chen Di, Cao Jiayi, Zheng Ying, Han Yuying, Jin Yirong, Wang Shuhui, Wang Ting, Ma Lin, Luo Tingting, Wang Yan, Qin Wen, Dong Lei
Department of Digestive Disease and Gastrointestinal Motility Research Room, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
Cancer Cell Int. 2022 Mar 4;22(1):102. doi: 10.1186/s12935-022-02522-0.
The role of CARM1 in tumors is inconsistent. It acts as an oncogene in most cancers but it inhibits the progression of liver and pancreatic cancers. CARM1 has recently been reported to regulate autophagy, but this function is also context-dependent. However, the effect of CARM1 on gastric cancer (GC) has not been studied. We aimed to explore whether CARM1 was involved in the progression of GC by regulating autophagy.
The clinical values of CARM1 and autophagy in GC were evaluated by immunohistochemistry and qRT-PCR. Transmission electron microscopy, immunofluorescence and western blotting were employed to identify autophagy. The role of CARM1 in GC was investigated by CCK-8, colony formation and flow cytometry assays in vitro and a xenograft model in vivo. Immunoprecipitation assays were performed to determine the interaction of CARM1 and TFE3.
CARM1 was upregulated in clinical GC tissues and cell lines, and higher CARM1 expression predicted worse prognosis. CARM1 enhanced GC cell proliferation, facilitated G1-S transition and inhibited ER stress-induced apoptosis by regulating autophagy. Importantly, treatment with a CARM1 inhibitor rescued the tumor-promoting effects of CARM1 both in vitro and in vivo. Furthermore, we demonstrated that CARM1 promoted TFE3 nuclear translocation to induce autophagy through the cytoplasmic AMPK-mTOR and nuclear AMPK-CARM1-TFE3 signaling pathways.
CARM1 promoted GC cell proliferation, accelerated G1-S transition and reduced ER stress-induced apoptosis by regulating autophagy. Mechanistically, CARM1 triggered autophagy by facilitating TFE3 nuclear translocation through the AMPK-mTOR and AMPK-CARM1-TFE3 signaling pathways.
CARM1在肿瘤中的作用并不一致。它在大多数癌症中作为一种癌基因起作用，但却抑制肝癌和胰腺癌的进展。最近有报道称CARM1可调节自噬，但这种功能也依赖于具体情况。然而，CARM1对胃癌（GC）的影响尚未得到研究。我们旨在探讨CARM1是否通过调节自噬参与GC的进展。
通过免疫组织化学和qRT-PCR评估CARM1和自噬在GC中的临床价值。采用透射电子显微镜、免疫荧光和蛋白质印迹法鉴定自噬。通过体外CCK-8、集落形成和流式细胞术检测以及体内异种移植模型研究CARM1在GC中的作用。进行免疫沉淀试验以确定CARM1与TFE3的相互作用。
CARM1在临床GC组织和细胞系中上调，较高的CARM1表达预示着更差的预后。CARM1通过调节自噬增强GC细胞增殖，促进G1-S期转换并抑制内质网应激诱导的凋亡。重要的是，用CARM1抑制剂治疗可在体外和体内挽救CARM1的促肿瘤作用。此外，我们证明CARM1通过细胞质AMPK-mTOR和细胞核AMPK-CARM1-TFE3信号通路促进TFE3核转位以诱导自噬。
CARM1通过调节自噬促进GC细胞增殖，加速G1-S期转换并减少内质网应激诱导的凋亡。机制上，CARM1通过AMPK-mTOR和AMPK-CARM1-TFE3信号通路促进TFE3核转位从而触发自噬。
