Faculty of Medicine, Jordan University of Science & Technology, Irbid, Jordan.
Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid, Jordan.
Medicine (Baltimore). 2023 Sep 8;102(36):e35004. doi: 10.1097/MD.0000000000035004.
Cell cycle regulatory proteins plays a pivotal role in the development and progression of many human malignancies. Identification of their biological functions as well as their prognostic utility presents an active field of research. As a continuation of the ongoing efforts to elucidate the molecular characteristics of clear cell renal cell carcinoma (ccRCC); we present a comprehensive bioinformatics study targeting the prognostic and mechanistic role of cyclin-dependent kinase inhibitor 3 (CDKN3) in ccRCC. The ccRCC cohort from the Cancer Genome Atlas Program was accessed through the UCSC Xena browser to obtain CDKN3 mRNA expression data and their corresponding clinicopathological variables. The independent prognostic signature of CDKN3 was evaluated using univariate and multivariate Cox logistic regression analysis. Gene set enrichment analysis and co-expression gene functional annotations were used to discern CDKN3-related altered molecular pathways. The tumor immune microenvironment was evaluated using TIMER 2.0 and gene expression profiling interactive analysis. CDKN3 upregulation is associated with shortened overall survival (hazard ratio [HR] = 2.325, 95% confident interval [CI]: 1.703-3.173, P < .0001) in the Cancer Genome Atlas Program ccRCC cohort. Univariate (HR: 0.426, 95% CI: 0.316-0.576, P < .001) and multivariate (HR: 0.560, 95% CI: 0.409-0.766, P < .001) Cox logistic regression analyses indicate that CDKN3 is an independent prognostic variable of the overall survival. High CDKN3 expression is associated with enrichment within the following pathways including allograph rejection, epithelial-mesenchymal transition, mitotic spindle, inflammatory response, IL-6/JAK/STAT3 signaling, spermatogenesis, TNF-α signaling via NF-kB pathway, complement activation, KRAS signaling, and INF-γ signaling. CDKN3 is also associated with significant infiltration of a wide spectrum of immune cells and correlates remarkably with immune-related genes. CDKN3 is a poor prognostic biomarker in ccRCC that alters many molecular pathways and impacts the tumor immune microenvironment.
细胞周期调控蛋白在许多人类恶性肿瘤的发生和发展中起着关键作用。鉴定它们的生物学功能及其预后效用是一个活跃的研究领域。作为阐明透明细胞肾细胞癌（ccRCC）分子特征的持续努力的延续；我们提出了一项针对细胞周期依赖性激酶抑制剂 3（CDKN3）在 ccRCC 中的预后和机制作用的综合生物信息学研究。通过 UCSC Xena 浏览器访问癌症基因组图谱计划中的 ccRCC 队列，以获取 CDKN3 mRNA 表达数据及其相应的临床病理变量。使用单变量和多变量 Cox 逻辑回归分析评估 CDKN3 的独立预后特征。使用基因集富集分析和共表达基因功能注释来辨别与 CDKN3 相关的改变的分子途径。使用 TIMER 2.0 和基因表达谱交互式分析评估肿瘤免疫微环境。CDKN3 的上调与癌症基因组图谱计划 ccRCC 队列中的总生存期缩短相关（危险比 [HR] = 2.325，95%置信区间 [CI]：1.703-3.173，P <.0001）。单变量（HR：0.426，95%CI：0.316-0.576，P <.001）和多变量（HR：0.560，95%CI：0.409-0.766，P <.001）Cox 逻辑回归分析表明，CDKN3 是总生存的独立预后变量。高 CDKN3 表达与以下途径的富集相关，包括同种异体排斥、上皮-间充质转化、有丝分裂纺锤体、炎症反应、IL-6/JAK/STAT3 信号、精子发生、TNF-α 信号通过 NF-kB 途径、补体激活、KRAS 信号和 INF-γ 信号。CDKN3 还与广泛的免疫细胞浸润显著相关，并与免疫相关基因显著相关。CDKN3 是 ccRCC 的预后不良生物标志物，它改变了许多分子途径，并影响肿瘤免疫微环境。
