Integrated systematic functional screen and fine-mapping decipher the role and genetic regulation of RPS19 in colorectal cancer development

IF 4.8 2区 医学 Q1 TOXICOLOGY Archives of Toxicology Pub Date : 2024-07-16 DOI:10.1007/s00204-024-03822-2
Can Chen, Wenzhuo Wang, Caibo Ning, Zequn Lu, Ming Zhang, Ying Zhu, Jianbo Tian, Haijie Li, Yue Ge, Beifang Yang, Xiaoping Miao
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Abstract

Despite genome-wide association studies (GWAS) have identified more than 200 risk loci associated with colorectal cancer (CRC), the causal genes or risk variants within these loci and their biological functions remain not fully revealed. Recently, the genomic locus 19q13.2, with the lead SNP rs1800469 was identified as a crucial CRC risk locus in Asian populations. However, the functional mechanism of this region has not been fully elucidated. Here we employed an RNA interfering-based on-chip approach to screen for the genes essential for cell proliferation in the CRC risk locus 19q13.2. Notably, we found that RPS19 exhibited the most significant effect among the identified genes and acted as a critical oncogene facilitating CRC cell proliferation. Subsequently, combining integrative fine-mapping analysis and a large-scale population study consisting of 6027 cases and 6099 controls, we prioritized rs1025497 as a potential causal candidate for CRC risk, demonstrating that rs1025497[A] allele significantly reduced the risk of CRC (OR 0.70, 95% confidence interval = 0.56–0.83, P = 1.12 × 10–6), which was further validated in UK Biobank cohort comprising 5,313 cases and 21,252 controls. Mechanistically, we experimentally elucidated that variant rs1025497 might acted as an allele-specific silencer, inhibiting the expression level of oncogene RPS19 mediated by the transcription suppressive factor HBP1. Taken together, our sturdy unveils the significant role of RPS19 during CRC pathogenesis and delineates its distal regulatory mechanism mediated by rs1025497, advancing our understanding of the etiology of CRC and provided new insights into the personalized medicine of human cancer.

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整合系统功能筛选和精细图谱,破解 RPS19 在结直肠癌发展中的作用和遗传调控。
尽管全基因组关联研究(GWAS)发现了 200 多个与结直肠癌(CRC)相关的风险位点,但这些位点中的致病基因或风险变异及其生物学功能仍未完全揭示。最近,以 SNP rs1800469 为首的基因组位点 19q13.2 被确定为亚洲人群中一个关键的 CRC 风险位点。然而,该区域的功能机制尚未完全阐明。在这里,我们采用了基于 RNA 干扰的芯片方法来筛选 CRC 风险位点 19q13.2 中对细胞增殖至关重要的基因。值得注意的是,我们发现 RPS19 在已发现的基因中具有最显著的影响,是促进 CRC 细胞增殖的关键癌基因。随后,结合综合精细图谱分析和由 6027 例病例和 6099 例对照组成的大规模人群研究,我们优先选择 rs1025497 作为 CRC 风险的潜在因果候选基因,结果表明 rs1025497[A] 等位基因可显著降低 CRC 风险(OR 0.70,95% 置信区间 = 0.56-0.83,P = 1.12 × 10-6),这一结果在由 5313 例病例和 21252 例对照组成的英国生物库队列中得到了进一步验证。从机理上讲,我们通过实验阐明了变异体rs1025497可能作为等位基因特异性沉默因子,抑制由转录抑制因子HBP1介导的癌基因RPS19的表达水平。综上所述,我们的研究揭示了 RPS19 在 CRC 发病过程中的重要作用,并阐明了 rs1025497 介导的远端调控机制,从而推进了我们对 CRC 病因学的理解,并为人类癌症的个体化医疗提供了新的见解。
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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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