A large-scale microRNA transcriptome-wide association study identifies two susceptibility microRNAs, miR-1307-5p and miR-192-3p, for colorectal cancer risk.
A large-scale microRNA transcriptome-wide association study identifies two susceptibility microRNAs, miR-1307-5p and miR-192-3p, for colorectal cancer risk.
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一项大规模 microRNA 全转录组关联研究确定了两种与结直肠癌风险相关的 microRNA（miR-1307-5p 和 miR-192-3p）。
DOI：
10.1093/hmg/ddad185
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发表时间：
2024
影响因子：
3.5
通讯作者：
Shi
中科院分区：
文献类型：
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作者：
Chen,Zhishan;Lin,Weiqiang;Cai,Qiuyin;Kweon,Sun-Seog;Shu,Xiao-Ou;Tanikawa,Chizu;Jia,Wei-Hua;Wang,Ying;Su,Xinwan;Yuan,Yuan;Wen,Wanqing;Kim,Jeongseon;Shin,Aesun;Jee,SunHa;Matsuo,Keitaro;Kim,Dong-Hyun;Wang,Nan;Ping,Jie;Shi
全转录组关联研究（TWAS）已经确定了许多推定的结直肠癌（CRC）风险易感基因。然而，易感性miRNAs，基因表达的关键失调，仍然没有探索。我们对来自313名CRC东亚患者的DNA样本进行基因分型，并在远离肿瘤的正常结肠组织中进行小RNA测序，以建立预测miRNA表达的遗传模型。我们应用这些模型和来自全基因组关联研究（GWAS）的数据，包括东亚血统的23942例病例和217267例对照，以研究预测的miRNA表达与CRC风险的相关性。分别在SW 480和HCT 116细胞中进行微扰实验，通过促进和抑制miRNAs的表达，并进一步进行体外分析。在Bonferroni校正阈值P < 4.5 × 10−4时，我们发现了两个假定的易感性miRNAs，miR-1307- 5和miR-192- 3 p，位于距离任何GWAS确定的CRC风险变体超过500 kb的区域。我们观察到miR-1307- 5 p的高预测表达与CRC风险增加相关，而miR-192- 3 p的低预测表达与CRC风险增加相关。我们的实验结果进一步提供了强有力的证据，通过显示miR-1307- 5和miR-192- 3 p分别在促进和抑制CRC细胞增殖、迁移和侵袭中发挥调节作用，这在SW 480和HCT 116细胞中一致地观察到。我们的研究为CRC发展的生物学机制提供了额外的见解。
Transcriptome-wide association studies (TWAS) have identified many putative susceptibility genes for colorectal cancer (CRC) risk. However, susceptibility miRNAs, critical dysregulators of gene expression, remain unexplored. We genotyped DNA samples from 313 CRC East Asian patients and performed small RNA sequencing in their normal colon tissues distant from tumors to build genetic models for predicting miRNA expression. We applied these models and data from genome-wide association studies (GWAS) including 23 942 cases and 217 267 controls of East Asian ancestry to investigate associations of predicted miRNA expression with CRC risk. Perturbation experiments separately by promoting and inhibiting miRNAs expressions and furtherin vitroassays in both SW480 and HCT116 cells were conducted. At a Bonferroni-corrected threshold ofP< 4.5 × 10−4, we identified two putative susceptibility miRNAs,miR-1307-5pandmiR-192-3p, located in regions more than 500 kb away from any GWAS-identified risk variants in CRC. We observed that a high predicted expression ofmiR-1307-5pwas associated with increased CRC risk, while a low predicted expression ofmiR-192-3pwas associated with increased CRC risk. Our experimental results further provide strong evidence of their susceptible roles by showing thatmiR-1307-5pandmiR-192-3pplay a regulatory role, respectively, in promoting and inhibiting CRC cell proliferation, migration, and invasion, which was consistently observed in both SW480 and HCT116 cells. Our study provides additional insights into the biological mechanisms underlying CRC development.