Wu Yuhui, Liang Xiaojing, Ni Junjie, Zhao Rongjie, Shao Shengpeng, Lu Si, Han Weidong, Yu Liangliang
Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Department of Breast and Thyroid Surgery, Jinhua Municipal Central Hospital, Jinhua, China.
Front Cell Dev Biol. 2021 Jul 19;9:681240. doi: 10.3389/fcell.2021.681240. eCollection 2021.
An increasing number of studies have shown that Isthmin 1 (ISM1), a secreted protein, is important in tumorigenesis and invasion, including in colorectal cancer (CRC). However, the mechanisms are still unclear. This study aims to explore the function and prognosis capacity of ISM1 in CRC. We investigated the expression of ISM1 in 18 CRC tissues vs. adjacent normal tissues from GSE50760, 473 CRC tissues vs. 41 normal tissues from The Cancer Genome Atlas (TCGA), and across gastrointestinal cancer types. Differences were further confirmed in CRC tissues via quantitative real-time polymerase chain reaction (qRT-PCR). Then, we analyzed correlations between clinicopathologic features and ISM1 expression, including prognostic prediction value, using the Kaplan-Meier method and multivariate Cox regression. Gene set enrichment analysis (GSEA) was performed to identify ISM1-related pathways. experiments were performed to verify the role of ISM1 in epithelial-mesenchymal transition (EMT) and CRC progression. Multiple datasets showed that ISM1 is upregulated in CRC tissues, which was validated. Patients with higher ISM1 expression had shorter overall survival (OS), and ISM1 expression served as an independent prognostic factor. Enrichment analysis showed that ISM1 upregulation was positively correlated with cancer-related pathways, such as EMT, hypoxia, and the Notch and KRAS signaling pathways. We were exclusively interested in the connection between ISM1 and EMT because 71% of genes in this pathway were significantly positively co-expressed with ISM1, which may account for why patients with higher ISM1 expression are prone to regional lymph node involvement and progression to advanced stages. In addition, we found that ISM1 was positively correlated with multiple immunosuppressive pathways such as IL2/STAT5, TNF-α/NF-κB, and TGF-β, and immune checkpoints, including PD-L1, PD-1, CTLA-4, and LAG3, which may account for upregulation of ISM1 in immunotherapy-resistant patients. Notably, through experiments, we found that ISM1 promoted EMT and colon cancer cell migration and proliferation. ISM1 is critical for CRC development and progression, which enhances our understanding of the low response rate of CRC to immunotherapy via immunosuppressive signaling pathways.
越来越多的研究表明，分泌蛋白Isthmin 1（ISM1）在肿瘤发生和侵袭中起重要作用，包括在结直肠癌（CRC）中。然而，其机制仍不清楚。本研究旨在探讨ISM1在CRC中的功能和预后能力。我们调查了来自GSE50760的18对CRC组织与相邻正常组织、来自癌症基因组图谱（TCGA）的473对CRC组织与41对正常组织以及不同胃肠道癌症类型中ISM1的表达情况。通过定量实时聚合酶链反应（qRT-PCR）在CRC组织中进一步证实了差异。然后，我们使用Kaplan-Meier法和多变量Cox回归分析了临床病理特征与ISM1表达之间的相关性，包括预后预测价值。进行基因集富集分析（GSEA）以确定与ISM1相关的途径。进行实验以验证ISM1在上皮-间质转化（EMT）和CRC进展中的作用。多个数据集显示ISM1在CRC组织中上调，这一结果得到了验证。ISM1表达较高的患者总生存期（OS）较短，且ISM1表达是一个独立的预后因素。富集分析表明，ISM1上调与癌症相关途径呈正相关，如EMT途径、缺氧途径以及Notch和KRAS信号通路。我们特别关注ISM1与EMT之间的联系，因为该途径中71%的基因与ISM1显著正共表达，这可能解释了为什么ISM1表达较高的患者容易发生区域淋巴结转移并进展至晚期。此外，我们发现ISM1与多种免疫抑制途径如IL2/STAT5、TNF-α/NF-κB和TGF-β以及免疫检查点包括PD-L1、PD-1、CTLA-4和LAG3呈正相关，这可能解释了免疫治疗耐药患者中ISM1上调的原因。值得注意的是，通过实验我们发现ISM1促进了EMT以及结肠癌细胞的迁移和增殖。ISM1对CRC的发生和进展至关重要，这加深了我们对CRC通过免疫抑制信号通路导致免疫治疗低反应率的理解。
