AUTHOR=Cai Jiajia , Chen Jianyun , Huang Ling , Wang Changxi , Zhang Weiyun , Zhou Quan , Sun Zhaohui 

TITLE=A TIMM17A Regulatory Network Contributing to Breast Cancer

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.658154

DOI=10.3389/fgene.2021.658154

ISSN=1664-8021

ABSTRACT=<sec><title>Background</title><p>Translocase of inner mitochondrial membrane 17A (<italic>TIMM17A</italic>) is overexpressed in breast cancer (BRCA), and upregulation can increase the aggressiveness of BRCA cells. This study examined the influence of the <italic>TIMM17A</italic> gene network on BRCA outcome.</p></sec><sec><title>Methods</title><p>Expression levels of <italic>TIMM17A</italic> were compared between normal and tumor tissues from the Oncomine<sup>TM</sup> database, and the association with patient survival was analyzed using Kaplan–Meier Plotter. Clinical factors influencing <italic>TIMM17A</italic> expression were studied by UALCAN. cBioPotal was then used to identify genes interacting with <italic>TIMM17A</italic>, and network relationships were assessed using the R clusterProfiler package. The association between <italic>TIMM17A</italic> 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, <italic>TIMM17A</italic> 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.</p></sec><sec><title>Results</title><p>Expression of <italic>TIMM17A</italic> was significantly elevated in BRCA compared with normal tissue (<italic>p</italic> &lt; 0.05), and overexpression was associated with both poor overall survival (OS) and shorter distant metastasis-free survival (DMFS) (<italic>p</italic> &lt; 0.05). Expression of <italic>TIMM17A</italic> was not associated with age, sex, BRCA subclass, clinical stage, or patient ethnicity. The coexpressed <italic>TIMM17A</italic> network was enriched in genes targeted by cell cycle regulators such as <italic>CDK1</italic>, <italic>miR-331</italic>, and <italic>E2F</italic> family transcription factors (<italic>FDR</italic> &lt; 0.001). Furthermore, flow cytometry revealed a strong association between higher <italic>TIMM17A</italic> expression and faster cell cycle progression in these BRCA cell lines. In addition, expression of <italic>TIMM17A</italic> protein was correlated with CDK1 protein expression in BRCA cell lines as measured by western blotting.</p></sec><sec><title>Conclusion</title><p>Elevated <italic>TIMM17A</italic> expression accelerates the progression of BRCA, thereby reducing OS and DMFS. The <italic>TIMM17A</italic>-associated networks identified here provide clues to the molecular pathogenesis of BRCA and potential targets for BRCA treatment.</p></sec>