Higuchi Satoshi, Otsu Hajime, Masuda Takaaki, Hashimoto Masahiro, Nakano Yusuke, Hosoda Kiyotaka, Hirose Kosuke, Ikehara Tomohiko, Ofuchi Takashi, Tsuda Yasuo, Yonemura Yusuke, Uemura Mamoru, Eguchi Hidetoshi, Doki Yuichiro, Mimori Koshi
Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumibaru, Beppu, Oita, 874-0838, Japan.
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
J Gastroenterol. 2025 May 25. doi: 10.1007/s00535-025-02259-3.
Intracellular calcium (Ca) signaling regulates key cancer processes. Research findings suggest that the SEC61 complex, involved in protein translocation, contributes to calcium leakage from the endoplasmic reticulum. However, the mechanism by which SEC61 Translocon Subunit Gamma (SEC61G), a component of this complex, influences colorectal cancer (CRC) progression remains unclear.
Bioinformatics analysis was performed using The Cancer Genome Atlas data sets to identify candidate genes on chromosome 7p, examine their association with DNA copy number amplification. In addition, SEC61G expression in CRC cells and tissues was validated using reverse-transcription quantitative polymerase chain reaction and immunohistochemistry. Moreover, in vitro and in vivo experiments were performed to investigate the effects of SEC61G overexpression and knockdown on CRC cell proliferation. Furthermore, publicly available single-cell RNA sequencing (scRNA-seq) and spatial transcriptome sequencing (ST-seq) data were used to validate the role of SEC61G in CRC.
SEC61G was significantly upregulated in CRC tissues and was correlated with poor prognosis in patients with CRC. SEC61G overexpression enhanced cell proliferation and activated the EGFR pathway, promoting cell cycle progression from the G1 to S phase. In addition, SEC61G overexpression increased cytosolic Ca levels, which activated EGFR signaling via calmodulin. Moreover, analyses of scRNA-seq and ST-seq data confirmed that SEC61G expression was higher in tumor epithelial cells and that it was co-expressed with EGFR pathway-related genes.
SEC61G promotes CRC progression by regulating cytosolic Ca concentration, EGFR activation, and cell cycle progression, highlighting its potential as a prognostic biomarker and therapeutic target in CRC.
细胞内钙（Ca）信号传导调节关键的癌症进程。研究结果表明，参与蛋白质转运的SEC61复合物会导致内质网钙泄漏。然而，该复合物的一个组成部分SEC61转运体亚基γ（SEC61G）影响结直肠癌（CRC）进展的机制仍不清楚。
使用癌症基因组图谱数据集进行生物信息学分析，以鉴定7号染色体上的候选基因，检查它们与DNA拷贝数扩增的关联。此外，使用逆转录定量聚合酶链反应和免疫组织化学验证CRC细胞和组织中SEC61G的表达。此外，进行体外和体内实验以研究SEC61G过表达和敲低对CRC细胞增殖的影响。此外，利用公开可用的单细胞RNA测序（scRNA-seq）和空间转录组测序（ST-seq）数据来验证SEC61G在CRC中的作用。
SEC61G在CRC组织中显著上调，并且与CRC患者的不良预后相关。SEC61G过表达增强细胞增殖并激活EGFR通路，促进细胞周期从G1期进展到S期。此外，SEC61G过表达增加了细胞质Ca水平，其通过钙调蛋白激活EGFR信号传导。此外，scRNA-seq和ST-seq数据分析证实，SEC61G在肿瘤上皮细胞中的表达更高，并且它与EGFR通路相关基因共表达。
SEC61G通过调节细胞质Ca浓度、EGFR激活和细胞周期进程促进CRC进展，突出了其作为CRC预后生物标志物和治疗靶点的潜力。
