Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation Research, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China.
The Third Clinical Medical College, Fujian Medical University, Fuzhou, 350122, China.
Cell Death Dis. 2023 Apr 6;14(4):245. doi: 10.1038/s41419-023-05767-3.
CMTR1, also called IFN-stimulated gene 95 kDa protein (ISG95), is elevated by viral infection in a variety of cells. However, the functions of CMTR1 in colorectal cancer (CRC), especially its roles in tumorigenesis and immune regulation, remain unclear. Here, we first identified CMTR1 as a novel oncogene in colorectal cancer. Based on The Cancer Genome Atlas (TCGA) database exploration and human tissue microarray (TMA) analysis, we found that CMTR1 expression was markedly higher in CRC tissues than in adjacent normal tissues. High CMTR1 expression was correlated with poor prognosis in CRC patients. Knockdown (KD) of CMTR1 significantly suppressed cell proliferation and tumorigenicity both in vitro and in vivo, whereas overexpression of CMTR1 resulted in the opposite effects. KEGG pathway analysis revealed differential enrichment in the JAK/STAT signaling pathway in colorectal cancer cells with CMTR1 KD. Mechanistically, suppression of CMTR1 expression inhibited RNAPII recruitment to the transcription start site (TSS) of STAT3 and suppressed STAT3 expression and activation. Furthermore, the efficacy of PD1 blockade immunotherapy was prominently enhanced in the presence of CMTR1 KD via increased infiltration of CD8 + T cells into the tumor microenvironment. Overall, it appears that CMTR1 plays a key role in regulating tumor cell proliferation and antitumor immunity.
CMTR1，也称为 IFN 刺激基因 95kDa 蛋白（ISG95），在多种细胞中被病毒感染所上调。然而，CMTR1 在结直肠癌（CRC）中的功能，特别是其在肿瘤发生和免疫调节中的作用，仍不清楚。在这里，我们首次鉴定 CMTR1 为结直肠癌中的一种新型癌基因。基于癌症基因组图谱（TCGA）数据库探索和人类组织微阵列（TMA）分析，我们发现 CMTR1 在 CRC 组织中的表达明显高于相邻正常组织。CMTR1 高表达与 CRC 患者的不良预后相关。CMTR1 的敲低（KD）显著抑制了体外和体内的细胞增殖和致瘤性，而 CMTR1 的过表达则产生了相反的效果。KEGG 通路分析显示，在 CMTR1 KD 的结直肠癌细胞中，JAK/STAT 信号通路存在差异富集。在机制上，CMTR1 表达的抑制抑制了 RNAPII 向 STAT3 的转录起始位点（TSS）的募集，并抑制了 STAT3 的表达和激活。此外，CMTR1 KD 显著增强了 PD1 阻断免疫疗法的疗效，通过增加 CD8+T 细胞浸润到肿瘤微环境中。总的来说，CMTR1 似乎在调节肿瘤细胞增殖和抗肿瘤免疫中发挥关键作用。
