Guo Pengli, Xu Chentong, Zhang Xuan, Feng Jinqiu, Lou Yaxin, Ye Shufang, Lv Ping, Zhu Bin, Chen Yingyu
Department of Immunology, Peking University School of Basic Medical Sciences; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China.
Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Beijing Pediatric Research Institute, Capital Medical University, National Center for Children's Health, Beijing, China.
FASEB J. 2024 Dec 15;38(23):e70217. doi: 10.1096/fj.202400833RRR.
ELMOD3 (encoding ELMO domain containing 3) is a causative gene associated with human autosomal dominant nonsyndromic and progressive hearing loss. However, the role of ELMOD3 in the occurrence and development of tumors remains unknown. Herein, we observed that inactivation of ELMOD3 in gastric cancer cells significantly inhibited their proliferation, migration, and invasion, and altered cell cycle progression. A xenograft tumor model showed that knockout of ELMOD3 suppressed the tumorigenicity of BGC823 gastric cancer cells in nude mice. Further investigation demonstrated that the ELMO domain of ELMOD3 interacts with β-catenin, which increases the levels of β-catenin, promoting downstream target gene expression. Deletion of ELMOD3 in gastric cells decreased the β-catenin signaling, elevated E-cadherin levels, suppressed RAF/MEK/ERK signal pathway, and disrupted the formation of F-actin cytoskeleton. These results led us to propose that ELMOD3 may participate in multiple biological processes in promoting the tumorigenesis of gastric cancer. It exerts a positive role in the regulation of gastric cancer cell proliferation and progression. Thus, ELMOD3 was identified as a potential tumor target, which deserves further investigation.
ELMOD3（编码含ELMO结构域蛋白3）是一种与人类常染色体显性非综合征性进行性听力损失相关的致病基因。然而，ELMOD3在肿瘤发生发展中的作用尚不清楚。在此，我们观察到胃癌细胞中ELMOD3失活显著抑制其增殖、迁移和侵袭，并改变细胞周期进程。异种移植肿瘤模型显示，敲除ELMOD3可抑制BGC823胃癌细胞在裸鼠中的致瘤性。进一步研究表明，ELMOD3的ELMO结构域与β-连环蛋白相互作用，增加β-连环蛋白水平，促进下游靶基因表达。胃细胞中ELMOD3缺失降低β-连环蛋白信号传导，提高E-钙黏蛋白水平，抑制RAF/MEK/ERK信号通路，并破坏F-肌动蛋白细胞骨架的形成。这些结果使我们提出，ELMOD3可能参与促进胃癌发生的多个生物学过程。它在胃癌细胞增殖和进展的调控中发挥积极作用。因此，ELMOD3被确定为一个潜在的肿瘤靶点，值得进一步研究。
