Department of Urology, The First Hospital of China Medical University, Shenyang 110001 Liaoning, China.
Department of Pain Medicine, The First Hospital of China Medical University, Shenyang 110001 Liaoning, China.
Biomed Pharmacother. 2021 Jun;138:111355. doi: 10.1016/j.biopha.2021.111355. Epub 2021 Mar 8.
As the transmembrane receptor of Netrin-1, the tumor suppressor gene Unc-5 Netrin Receptor C (UNC5C) can trigger apoptosis. Although its tumor suppressor effects have been demonstrated in solid tumors such as colon cancer, there is still a lack of systematic research on its expression regulation mechanism. To address this need, we analyzed datasets from The Cancer Genome Atlas (TCGA) database, including multi-omics data for 32 types of cancers and 10,967 cases. Analysis of these data revealed a trend of significantly decreased UNC5C expression in 16 types of solid tumors. Additionally, low UNC5C expression is related to poor prognosis of five types of tumors and restoring the expression of UNC5C can effectively inhibit the proliferation potential of renal cancer cells. Promoter DNA methylation, chromatin remodeling-mediated epigenetic regulation, transcriptional inhibition, RNA-binding protein and miRNA-mediated post-transcriptional inhibition, genetic changes caused by deep deletion and truncated mutations, and ubiquitinating enzyme-mediated protein degradation can synergistically cause the down-regulation of UNC5C expression in solid tumors. This study is the first to analyze the comprehensive molecular mechanism of down-regulation of the tumor suppressor gene UNC5C from multiple dimensions using pan-cancer data. Our results suggest that analyses of gene expression regulation relying on computational biological methods may help guide the targeted therapy of tumor suppressor gene reactivation.
作为 Netrin-1 的跨膜受体，肿瘤抑制基因 Unc-5 Netrin 受体 C（UNC5C）可以触发细胞凋亡。尽管其在结肠癌等实体瘤中的肿瘤抑制作用已得到证实，但对于其表达调控机制仍缺乏系统研究。为了解决这一需求，我们分析了来自癌症基因组图谱（TCGA）数据库的数据集，包括 32 种癌症和 10967 例的多组学数据。对这些数据的分析表明，在 16 种实体瘤中 UNC5C 的表达呈显著下降趋势。此外，UNC5C 表达水平低与五种肿瘤的预后不良相关，恢复 UNC5C 的表达可有效抑制肾癌细胞的增殖潜力。启动子 DNA 甲基化、染色质重塑介导的表观遗传调控、转录抑制、RNA 结合蛋白和 miRNA 介导的转录后抑制、深缺失和截断突变引起的遗传变化以及泛素化酶介导的蛋白降解可协同导致 UNC5C 在实体瘤中的表达下调。这项研究首次从多个维度利用泛癌数据分析了肿瘤抑制基因 UNC5C 下调的综合分子机制。我们的研究结果表明，依赖于计算生物学方法的基因表达调控分析可能有助于指导肿瘤抑制基因再激活的靶向治疗。
