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Abstract：
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 risk-associated 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.
摘要：
本研究旨在研究circRNAs和相关遗传变异与前列腺癌（PCa）风险的关联，并阐明这种关联的生物学机制。通过使用MiOncoCirc数据库，我们首先比较了25个配对PCa和邻近正常组织之间circRNAs的表达水平,以确定风险相关的circRNAs.然后，我们使用逻辑回归模型来评估4662名前列腺癌患者和3114名健康对照中候选circRNAs中的遗传变异与PCa风险之间的关联。并确定cirHIBADHrs11973492为显性遗传模型中的显着风险相关变体（比值比=1.20，95％置信区间：1.08-1.34，P=7.06×10-4），改变了相应RNA链的二级结构。在计算机模拟分析中，我们发现cirHIBADH海绵和沉默21RNA结合蛋白（RPBs）富集在RNA剪接途径，其中使用外部RNA测序数据以及内部(4个组织样本)和公开的单细胞转录组鉴定并验证了HNRNPA1为中心RBP.此外,我们证明了HNRNPA1可能会影响包括MYC在内的标志，DNA修复,和E2F靶信号通路，从而促进致癌作用。总之,cirHIBADH的遗传变异可能是RNA剪接相关RBPs(包括HNRNPA1)的海绵和抑制剂,在PCa中起致癌作用.
