Department of Environmental Genomics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center of Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, Jiangsu, China.
J Gastroenterol. 2019 Nov;54(11):939-949. doi: 10.1007/s00535-019-01571-z. Epub 2019 Mar 28.
Oxaliplatin (L-OHP) is a commonly used first-line chemotherapy for colorectal cancer. Genetic variants in nucleotide excision repair (NER) pathway genes may alter genomic integrity and the efficacy of oxaliplatin-based chemotherapy in colorectal cancer.
We investigated the association between genetic variants in 19 NER pathway genes and the disease control rate (DCR) and progression-free survival (PFS) among 166 colorectal cancer patients who received oxaliplatin-based chemotherapy. Expression quantitative trait loci (eQTL) analysis was performed using the Genotype-Tissue Expression (GTEx) portal. Gene harboring significant SNP was overexpressed or knocked down to demonstrate the effect on cell phenotypes with or without oxaliplatin treatment.
We found that rs5030740, located in the 3'-untranslated region (3'-UTR) of RPA1, was associated with DCR [OR = 2.99 (1.33-5.69), P = 4.00 × 10] and PFS [HR = 1.86 (1.30-2.68), P = 7.39 × 10]. The C allele was significantly associated with higher RPA1 mRNA expression levels according to eQTL analysis (P = 0.010 for sigmoid colon and P = 0.004 for transverse colon). The C allele of rs5030740 disrupted let-7e-5p binding to enhance RPA1 expression. Functionally, RPA1 knockdown inhibited cell proliferation and promoted cell apoptosis, whereas RPA1 overexpression promoted proliferation and suppressed apoptosis. Furthermore, low RPA1 expression increased sensitivity to oxaliplatin in colon cancer cells and inhibited proliferation after oxaliplatin treatment.
Our findings demonstrate an association between rs5030740 and the DCR and PFS of colorectal cancer patients. RPA1 functions as a putative oncogene in tumorigenesis by reducing sensitivity to oxaliplatin and could serve as a potential prognostic biomarker in colorectal cancer.
奥沙利铂（L-OHP）是结直肠癌常用的一线化疗药物。核苷酸切除修复（NER）途径基因中的遗传变异可能会改变基因组的完整性，并影响结直肠癌中基于奥沙利铂的化疗效果。
我们研究了 19 个 NER 途径基因中的遗传变异与 166 例接受基于奥沙利铂化疗的结直肠癌患者的疾病控制率（DCR）和无进展生存期（PFS）之间的关系。使用基因型-组织表达（GTEx）门户进行表达数量性状基因座（eQTL）分析。对含有显著 SNP 的基因进行过表达或敲低，以证明在有无奥沙利铂治疗的情况下对细胞表型的影响。
我们发现，位于 RPA1 3'非翻译区（3'-UTR）的 rs5030740 与 DCR [比值比（OR）=2.99（1.33-5.69），P=4.00×10]和 PFS [风险比（HR）=1.86（1.30-2.68），P=7.39×10]相关。根据 eQTL 分析，C 等位基因与 RPA1 mRNA 表达水平显著相关（乙状结肠 P=0.010，横结肠 P=0.004）。rs5030740 的 C 等位基因破坏了 let-7e-5p 与 RPA1 的结合，从而增强了 RPA1 的表达。功能上，RPA1 敲低抑制了细胞增殖并促进了细胞凋亡，而 RPA1 过表达促进了增殖并抑制了凋亡。此外，低 RPA1 表达增加了结肠癌细胞对奥沙利铂的敏感性，并抑制了奥沙利铂治疗后的增殖。
我们的研究结果表明，rs5030740 与结直肠癌患者的 DCR 和 PFS 相关。RPA1 通过降低对奥沙利铂的敏感性而在肿瘤发生中发挥潜在致癌基因的作用，可作为结直肠癌的潜在预后生物标志物。
