Rs7911488 modified the efficacy of capecitabine-based therapy in colon cancer through altering miR-1307-3p and TYMS expression

Abstract

Capecitabine is an orally administered prodrug of 5-fluouracil (5-FU) and is used in first-line treatment of metastatic colorectal cancer. Studies have demonstrated that polymorphisms in 5-FU related ADME genes are associated with the efficacy of capecitabine. However, the relationship between the polymorphisms within the microRNA precursors and the efficacy of capecitabine is still largely unknown. We detected six polymorphisms in 274 colon cancer patients and statistically analyzed the association of the genotypes with the efficacy of capecitabine-based chemotherapy. The mechanisms underlying the effect of genotypes on the efficacy of capecitabine were also studied. We identified a polymorphism rs7911488 T>C in pre-miR-1307 to be significantly associated with the efficacy of capecitabine chemotherapy in colon cancer patients. The response rates of capecitabine chemotherapy for the patients with TT, TC, and CC genotypes were 44.35% (55/124), 51.33% (58/113), and 24.32% (9/37), respectively. In the C-allelic patients, miR-1307-3p is down-regulated and TYMS, a direct target of miR-1307-3p, is over-expressed, which leads to insensitivity of cancer cells to capecitabine chemotherapy. The cancer cells with rs7911488 C allele were further observed to be resistant to 5-FU treatment in vitro and in vivo. Our findings show that rs7911488 C-allelic pre-miR-1307 leads to attenuated miR-1307-3p and elevated TYMS, thus insensitive to capecitabine chemotherapy in colon cancer.