Shuwei Li1,2, Kaili Xu1,2, Dongying Gu3, Lei He4, Lisheng Xie1,2, Zhengxin Chen5, Zhimin Fan4, Lingjun Zhu6, Mulong Du1,7, Haiyan Chu1,2, Zhengdong Zhang1,2, Yuan Wu8, Min Ni9, Meilin Wang10,11. 1. 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. 2. 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. 3. Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. 4. Department of Colorectal Surgery, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210001, China. 5. First School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China. 6. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 7. Department of Biostatistics, Nanjing Medical University, Nanjing, China. 8. Department of Medical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China. wu@njmu.edu.cn. 9. Department of Colorectal Surgery, The Third Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210001, China. niminnj@163.com. 10. 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. mwang@njmu.edu.cn. 11. 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. mwang@njmu.edu.cn.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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 × 10-3] and PFS [HR = 1.86 (1.30-2.68), P = 7.39 × 10-4]. 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. CONCLUSIONS: 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.
BACKGROUND: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. METHODS: 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 cancerpatients 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. RESULTS: 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 × 10-3] and PFS [HR = 1.86 (1.30-2.68), P = 7.39 × 10-4]. 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. CONCLUSIONS: Our findings demonstrate an association between rs5030740 and the DCR and PFS of colorectal cancerpatients. RPA1 functions as a putative oncogene in tumorigenesis by reducing sensitivity to oxaliplatin and could serve as a potential prognostic biomarker in colorectal cancer.
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