Lu Lu, Guo Guoqing, Guo Jiahao, Li Hanyang, Chen Kexin, Chen Yuli, Li Qiuhui, Li Qiunuo, Diao Yuhao, Sun Ming, Wu Hao, Liu Xianghua
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
Suzhou Cancer Center Core Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China.
Cell Death Discov. 2025 Jul 29;11(1):350. doi: 10.1038/s41420-025-02644-0.
Gastric cancer (GC), a malignant neoplasm originating in the stomach epithelium, is characterized by substantial global incidence and mortality rates, posing a substantial threat to public health systems worldwide. The present study was designed to identify and validate a previously unannotated protein encoded by circular RNA (circRNA), with the principal objective of elucidating its functional significance and mechanistic basis in gastric carcinogenesis.CircUBE2G1 (hsa_circ_003239) was identified as a translationally active circRNA exhibiting significant downregulation in gastric cancer. The novel protein product derived from circUBE2G1 translation, designated circUBE2G1-99aa, was confirmed through co-immunoprecipitation coupled with tandem mass spectrometry (LC-MS/MS), representing the first documentation of its existence in human malignancies.CircUBE2G1-99aa exhibited marked downregulation in gastric cancer (GC), with its diminished expression levels demonstrating significant correlations with larger primary tumor size, lymph node metastasis, and advanced TNM stages. Functionally, circUBE2G1 exerted tumor-suppressive effects via its encoded protein circUBE2G1-99aa, not the full-length RNA, by inhibiting GC cell proliferation in vitro and in vivo. Mechanistically, circUBE2G1-99aa directly bound ENO1 and suppressed its glycolytic activity, thereby reducing glycolysis in GC cells. These findings delineate the functional and mechanistic landscape of circUBE2G1-99aa in gastric cancer, proposing its dual utility as both a prognostic biomarker and therapeutic target in clinical oncology.
胃癌（GC）是一种起源于胃上皮的恶性肿瘤，其全球发病率和死亡率都很高，对全球公共卫生系统构成了重大威胁。本研究旨在鉴定和验证一种以前未注释的环状RNA（circRNA）编码的蛋白质，主要目的是阐明其在胃癌发生中的功能意义和机制基础。CircUBE2G1（hsa_circ_003239）被鉴定为一种具有翻译活性的circRNA，在胃癌中显著下调。通过免疫共沉淀结合串联质谱（LC-MS/MS）证实了源自circUBE2G1翻译的新型蛋白质产物，命名为circUBE2G1-99aa，这是其在人类恶性肿瘤中存在的首次记录。CircUBE2G1-99aa在胃癌（GC）中显著下调，其表达水平的降低与更大的原发肿瘤大小、淋巴结转移和晚期TNM分期显著相关。在功能上，circUBE2G1通过其编码的蛋白质circUBE2G1-99aa而非全长RNA发挥肿瘤抑制作用，在体外和体内抑制GC细胞增殖。机制上，circUBE2G1-99aa直接结合ENO1并抑制其糖酵解活性，从而减少GC细胞中的糖酵解。这些发现描绘了circUBE2G1-99aa在胃癌中的功能和机制图景，提出了其作为临床肿瘤学中预后生物标志物和治疗靶点的双重用途。
