A TIMM17A Regulatory Network Contributing to Breast Cancer.

Translocase of inner mitochondrial membrane 17A (TIMM17A) is overexpressed in breast cancer (BRCA), and upregulation can increase the aggressiveness of BRCA cells. This study examined the influence of the TIMM17A gene network on BRCA outcome. Expression levels of TIMM17A were compared between normal and tumor tissues from the OncomineTM database, and the association with patient survival was analyzed using Kaplan–Meier Plotter. Clinical factors influencing TIMM17A expression were studied by UALCAN. cBioPotal was then used to identify genes interacting with TIMM17A, and network relationships were assessed using the R clusterProfiler package. The association between TIMM17A mutation and mRNA expression in BRCA was examined using the LinkFinder application in LinkedOmics, and coexpressed genes were assessed for functional enrichment using the LinkInterpreter application. Furthermore, TIMM17A expression correlation with cell cycle phase distribution was performed by flow cytometry. Finally, the target networks of kinases, microRNAs (miRNAs), and transcription factors were identified using GeneMANIA. The expression and correlation of potential miRNAs and targets were further validated in BRCA cell lines by qRT-PCR. Expression of TIMM17A was significantly elevated in BRCA compared with normal tissue (p < 0.05), and overexpression was associated with both poor overall survival (OS) and shorter distant metastasis-free survival (DMFS) (p < 0.05). Expression of TIMM17A was not associated with age, sex, BRCA subclass, clinical stage, or patient ethnicity. The coexpressed TIMM17A network was enriched in genes targeted by cell cycle regulators such as CDK1, miR-331, and E2F family transcription factors (FDR < 0.001). Furthermore, flow cytometry revealed a strong association between higher TIMM17A expression and faster cell cycle progression in these BRCA cell lines. In addition, expression of TIMM17A protein was correlated with CDK1 protein expression in BRCA cell lines as measured by western blotting. Elevated TIMM17A expression accelerates the progression of BRCA, thereby reducing OS and DMFS. The TIMM17A-associated networks identified here provide clues to the molecular pathogenesis of BRCA and potential targets for BRCA treatment.

线粒体内膜转位酶17A（TIMM17A）在乳腺癌（BRCA）中过表达，其上调可增加BRCA细胞的侵袭性。本研究探讨了TIMM17A基因网络对BRCA预后的影响。 从Oncomine™数据库比较正常组织和肿瘤组织中TIMM17A的表达水平，并使用Kaplan - Meier Plotter分析其与患者生存率的关联。通过UALCAN研究影响TIMM17A表达的临床因素。然后使用cBioPotal识别与TIMM17A相互作用的基因，并使用R clusterProfiler软件包评估网络关系。使用LinkedOmics中的LinkFinder应用程序检查BRCA中TIMM17A突变与mRNA表达之间的关联，并使用LinkInterpreter应用程序对共表达基因进行功能富集评估。此外，通过流式细胞术分析TIMM17A表达与细胞周期时相分布的相关性。最后，使用GeneMANIA识别激酶、微小RNA（miRNAs）和转录因子的靶标网络。通过实时定量聚合酶链反应（qRT - PCR）在BRCA细胞系中进一步验证潜在miRNAs及其靶标的表达和相关性。 与正常组织相比，TIMM17A在BRCA中的表达显著升高（p < 0.05），过表达与总生存期（OS）较差和无远处转移生存期（DMFS）较短均相关（p < 0.05）。TIMM17A的表达与年龄、性别、BRCA亚型、临床分期或患者种族无关。共表达的TIMM17A网络富含细胞周期调节因子如CDK1、miR - 331和E2F家族转录因子所靶向的基因（错误发现率< 0.001）。此外，流式细胞术显示在这些BRCA细胞系中，TIMM17A较高表达与细胞周期进展更快之间存在强关联。此外，通过蛋白质印迹法检测，BRCA细胞系中TIMM17A蛋白的表达与CDK1蛋白的表达相关。 TIMM17A表达升高加速BRCA的进展，从而降低OS和DMFS。此处确定的与TIMM17A相关的网络为BRCA的分子发病机制和BRCA治疗的潜在靶点提供了线索。