Experimental Research Center, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China.
Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Mol Carcinog. 2024 Sep;63(9):1669-1681. doi: 10.1002/mc.23752. Epub 2024 May 30.
Interferon regulatory factor (IRF) family genes play a critical role in colorectal cancer (CRC) development and impact patient survival. This study evaluated the influence of functional single nucleotide polymorphisms (SNPs) in IRF genes on CRC survival, including functional predictions and experimental validations. Multivariate Cox regression analysis identified three linked SNPs as significant survival predictors, with the rs141112353 T/T genotype in the 3'UTR region of IRF6 significantly associated with decreased survival (HR = 1.60, P = 6E-04). Expression quantitative trait loci (eQTL) analysis indicated that the rs141112353 TA > T alteration reduced IRF6 expression. Dual luciferase assays showed lower activity for the T allele in the presence of hsa-miR-548ap-3p. Data from The Cancer Genome Atlas (TCGA) and other databases confirmed lower IRF6 levels in CRC tissues, correlating with worse survival and inversely with M2 macrophage infiltration. In vitro, IRF6 overexpression inhibited CRC cell proliferation and M2 macrophage polarization by downregulating MIF expression. These findings suggest that the IRF6 rs141112353 TA > T variant significantly affects CRC survival, potentially by enhancing miR-548-ap-3p binding affinity.
干扰素调节因子 (IRF) 家族基因在结直肠癌 (CRC) 的发展中起着关键作用，并影响患者的生存。本研究评估了 IRF 基因中功能性单核苷酸多态性 (SNP) 对 CRC 生存的影响，包括功能预测和实验验证。多变量 Cox 回归分析确定了三个连锁 SNP 作为显著的生存预测因子，IRF6 3'UTR 区域的 rs141112353 T/T 基因型与生存时间缩短显著相关 (HR=1.60，P=6E-04)。表达数量性状基因座 (eQTL) 分析表明，rs141112353 TA>T 改变降低了 IRF6 的表达。双荧光素酶报告基因实验表明，hsa-miR-548ap-3p 的存在降低了 T 等位基因的活性。来自癌症基因组图谱 (TCGA) 和其他数据库的数据证实 CRC 组织中 IRF6 水平较低，与生存时间更差相关，与 M2 巨噬细胞浸润呈负相关。在体外，IRF6 的过表达通过下调 MIF 表达抑制 CRC 细胞增殖和 M2 巨噬细胞极化。这些发现表明，IRF6 rs141112353 TA>T 变体显著影响 CRC 的生存，可能通过增强 miR-548ap-3p 的结合亲和力。
