Genetic variation of circHIBADH enhances prostate cancer risk through regulating HNRNPA1-related RNA splicing  

作　　者：Yifei Cheng Rongjie Shi Shuai Ben Silu Chen Shuwei Li Junyi Xin Meilin Wang Gong Cheng 

机构地区：[1]Department of Environmental Genomics,Jiangsu Key Laboratory of Cancer Biomarkers,Prevention and Treatment,Collaborative Innovation Center for Cancer Personalized Medicine,Nanjing Medical University,Nanjing,Jiangsu 211166,China [2]Department of Urology,the First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu 210029,China [3]Department of Bioinformatics,School of Biomedical Engineering and Informatics,Nanjing Medical University,Nanjing,Jiangsu 211166,China [4]Jiangsu Cancer Hospital,Jiangsu Institute of Cancer Research,the Affiliated Cancer Hospital of Nanjing Medical University,Nanjing,Jiangsu 210009,China [5]The Affiliated Suzhou Hospital of Nanjing Medical University,Suzhou Municipal Hospital,Gusu School,Nanjing Medical University,Suzhou,Jiangsu 215002,China

出　　处：《Journal of Biomedical Research》2024年第4期358-368,共11页生物医学研究杂志（英文版）

基　　金：supported by the Medical Research Project of Jiangsu Commission of Health(Grant No.M2022015).

摘　　要：The current study aimed to investigate associations of circRNAs and related genetic variants with the risk of prostate cancer(PCa)as well as to elucidate biological mechanisms underlying the associations.We first compared expression levels of circRNAs between 25 paired PCa and adjacent normal tissues to identify riskassociated circRNAs by using the MiOncoCirc database.We then used logistic regression models to evaluate associations between genetic variants in candidate circRNAs and PCa risk among 4662 prostate cancer patients and 3114 healthy controls,and identified circHIBADH rs11973492 T>C as a significant risk-associated variant(odds ratio=1.20,95%confidence interval:1.08-1.34,P=7.06×10^(-4))in a dominant genetic model,which altered the secondary structure of the corresponding RNA chain.In the in silico analysis,we found that circHIBADH sponged and silenced 21 RNA-binding proteins(RBPs)enriched in the RNA splicing pathway,among which HNRNPA1 was identified and validated as a hub RBP using an external RNA-sequencing data as well as the in-house(four tissue samples)and publicly available single-cell transcriptomes.Additionally,we demonstrated that HNRNPA1 influenced hallmarks including MYC target,DNA repair,and E2F target signaling pathways,thereby promoting carcinogenesis.In conclusion,genetic variants in circHIBADH may act as sponges and inhibitors of RNA splicing-associated RBPs including HNRNPA1,playing an oncogenic role in PCa.

关 键 词：genetic variants prostate cancer circRNA RNA-binding protein RNA splicing sing-cell RNA sequencing 

分 类 号：R737.25[医药卫生—肿瘤]