Abstract
Recent studies have identified that long noncoding RNA (lncRNA) might affect the responses to anticancer drug treatment, including colorectal cancer (CRC). However, the association between single-nucleotide polymorphisms (SNPs) in PVT1 and the chemotherapy response in metastatic colorectal cancer has yet to be clarified. In this study, the PVT1 rs2278176 CT/TT genotypes were found to be associated with an increased overall survival (OS) and progression-free survival (PFS) compared with the CC genotype. Furthermore, patients harboring the rs2278176 CT/TT genotypes had a greater chance of achieving clinical benefit from 5-Fluorouracil/leucovorin combined with oxaliplatin (FOLFOX). In vivo nude mice experiments demonstrated that the CRISPR/Cas9 mediated rs2278176 C to T mutation significantly inhibited the tumorigenesis of colorectal cancer cells treated with 5-Fu, but not control DMSO treated cells. Furthermore, the apoptotic rate was significantly enhanced by treatment with 5-Fu in the CRC cells carrying with the CT/TT genotypes. Functional studies demonstrated that the PVT1 rs2278176 C to T mutation altered the binding site for hsa-miR-297, and that hsa-miR-297 downregulated Glutathione S-Transferase Alpha 2(GSTA2), a member of phase II detoxification enzyme, in an Argonaute 2(Ago2)-dependent manner. Moreover, GSTA2 levels were downregulated in the cancer tissues of patients carrying rs2278176 CT/TT genotypes. High GSTA2 expression predicted poor clinical outcome in metastatic colorectal cancer treated with FOLFOX. In conclusion, this study provided that PVT1 with rs2278176 T allele altered the binding affinity with hsa-miR-297, leading to decreased GSTA2 expression and sensitized CRC cells to FOLFOX chemotherapy, suggesting rs2278176 CT/TT genotypes might serve as a predictive biomarker to improve prognosis in patients with metastatic CRC treated with FOLFOX.