MECOM 基因座是在高级别浆液性卵巢癌 (HGSOC) 中频繁扩增的基因。然而，检查 MECOM 转录本、患者预后及其在调节肿瘤免疫微环境 (TIME) 中的作用之间的关联的研究仍然很少，特别是在大型队列中。本研究评估了 GTEx/TCGA 联合数据库中 352 名 HGSOC 患者和 88 名正常卵巢组织中 MECOM 转录本的表达。使用 UCSC 基因组浏览器、Ensembl 和 NextProt 等资源，鉴定了与 MECOM 的经典蛋白质亚型相对应的两个转录本。采用 Cox 比例风险回归分析、Kaplan-Meier 生存曲线和综合 TIME 评估算法来阐明这些转录本的表达水平与患者预后和 TIME 状态之间的联系。分析了两种蛋白质异构体的染色质免疫沉淀测序 (ChIP-seq) 数据以及靶向沉默后的 RNA 测序数据，以确定不同转录因子的潜在调控靶点。 MECOM 亚型转录物的表达升高与 HGSOC 患者的较差生存率相关，这可能是通过调节癌症相关成纤维细胞 (CAF) 和免疫抑制细胞群来实现的。相比之下，较高水平的EVI1亚型转录物与生存率提高有关，这可能是由于CD8 T细胞、巨噬细胞的调节以及JUN蛋白表达或其下游基因的DNA结合活性的降低所致。研究发现，源自 MECOM 的多种蛋白质亚型通过特定机制对卵巢癌患者的生存和肿瘤发展产生不同的影响。研究疾病发病机制的分子机制并在剪接变异亚型水平上识别潜在的药物靶蛋白被认为至关重要。© 2024。作者。

The MECOM locus is a gene frequently amplified in high-grade serous ovarian carcinoma (HGSOC). Nevertheless, the body of research examining the associations among MECOM transcripts, patient prognosis, and their role in modulating the tumor immune microenvironment (TIME) remains sparse, particularly in large cohorts. This study assessed the expression of MECOM transcripts in 352 HGSOC patients and 88 normal ovarian tissues from the combined GTEx/TCGA database. Using resources such as the UCSC Genome Browser, Ensembl, and NextProt, two transcripts corresponding to classical protein isoforms from MECOM were identified. Cox proportional hazards regression analysis, Kaplan-Meier survival curves, and a comprehensive TIME evaluation algorithm were employed to elucidate the connections between the expression levels of these transcripts and both patient prognosis and TIME status. Chromatin Immunoprecipitation sequencing (ChIP-seq) data for the two protein isoforms, as well as RNA sequencing data post-targeted silencing, were analyzed to identify potential regulatory targets of the different transcription factors. Elevated expression of the MECOM isoform transcripts was correlated with poorer survival in HGSOC patients, potentially through the modulation of cancer-associated fibroblasts (CAFs) and immunosuppressive cell populations. In contrast, higher levels of EVI1 isoform transcripts were linked to enhanced survival, possibly due to the regulation of CD8+ T cells, macrophages, and a reduction in the expression of JUN protein, or its DNA-binding activity on downstream genes. Diverse protein isoforms derived from MECOM were found to differentially affect the survival and tumor development in ovarian cancer patients through specific mechanisms. Investigating the molecular mechanisms underlying disease pathogenesis and identifying potential drug target proteins at the level of splice variant isoforms were deemed crucial.© 2024. The Author(s).