Dataset Information

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.

SUBMITTER: Chen Q

PROVIDER: S-EPMC5650342 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Chen Qi Q Mao Yong Y Meng Fanyi F Wang Lei L Zhang Hongjian H Wang Weipeng W Hua Dong D

Oncotarget 20170728 43

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 associa ...[more]

PMID: 29088787

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Project description:BackgroundOur previous study has identified a novel circRNA (circDIDO1) that is down-regulated in gastric cancer (GC) and significantly inhibits GC progression. The purpose of this study is to identify the molecular mechanism for circDIDO1 and to evaluate the therapeutic effect of circDIDO1 in GC.MethodsBy combining bioinformatic analysis with RNA sequencing data, we predicted the potential target of circDIDO1 and further validated the regulatory mechanisms for its tumor suppressor function in GC. RIP assay, luciferase reporter assay and in vitro cell function assays were performed to analyze circDIDO1-regulated downstream target genes. For the therapeutic study, circDIDO1-loaded, RGD-modified exosomes (RGD-Exo-circDIDO1) were constructed and its anti-tumor efficacy and biological safety were evaluated in vitro and in vivo.ResultsCircDIDO1 inhibited GC progression by regulating the expression of the signal transducer inhibitor SOSC2 through sponging miR-1307-3p. Overexpression of circDIDO1 or SOSC2 antagonized the oncogenic role of miR-1307-3p. RGD-Exo-circDIDO1 could efficiently deliver circDIDO1 to increase SOCS2 expression in GC cells. Compared with PBS and RGD-Exo-vector treatment, RGD-Exo-circDIDO1 treatment significantly inhibited the proliferation, migration and invasion of GC cells while promoted cell apoptosis. The therapeutic efficacy of RGD-Exo-circDIDO1 was further confirmed in a mouse xenograft tumor model. In addition, major tissues including the heart, liver, spleen, lungs and kidneys showed no obvious histopathological abnormalities or lesions in the RGD-Exo-circDIDO1 treated group.ConclusionOur findings revealed that circDIDO1 suppressed the progression of GC via modulating the miR-1307-3p/SOSC2 axis. Systemic administration of RGD modified, circDIDO1 loaded exosomes repressed the tumorigenicity and aggressiveness of GC both in vitro and in vivo, suggesting that RGD-Exo-circDIDO1 could be used as a feasible nanomedicine for GC therapy.

Project description:BACKGROUND:Breast cancer is a global problem, and a large number of new cases are diagnosed every year. Capecitabine is effective in patients with metastatic breast cancer (MBC). Hand-foot syndrome (HFS) is a common adverse effect of capecitabine. In this study, we investigated the association between single nucleotide polymorphisms (SNPs) in genes involved in capecitabine metabolism pathways and capecitabine-induced HFS in Chinese patients with MBC to identify some predictive genetic biomarkers. METHODS:We selected 3 genes involved in capecitabine metabolism and screened genetic variants in these target genes. We genotyped a total of 22 SNPs in the thymidylate synthase gene (TYMS), the methylene tetrahydrofolate reductase gene (MTHFR), and the ribonucleotide reductase M1 gene (RRM1) in 342 MBC patients treated with capecitabine-based chemotherapy. The genotype distributions of each SNP in patients with and without HFS were assessed using Pearson's ?2 test, and the relationship between HFS and genotypes of SNPs was determined using logistic regression analysis. The association between SNPs and their corresponding gene expression was analyzed using the Blood expression quantitative trait loci (eQTL) browser online tools. RESULTS:We found 4 positive sites for HFS in the TYMS and MTHFR genes: TYMS rs2606241 (P?=?0.022), TYMS rs2853741 (P?=?0.019), MTHFR rs3737964 (P?=?0.029), and MTHFR rs4846048 (P?=?0.030). Logistic regression analyses showed that the genotype AG of MTHFR rs3737964 [odds ratio (OR)?=?0.54, 95% confidence interval (CI) 0.31-0.97, P?=?0.038] and MTHFR rs4846048 (OR?=?0.54, 95% CI 0.30-0.98, P?=?0.042) were protective factors of HFS, whereas the genotype CT of TYMS rs2853741 (OR?=?2.25, 95% CI 1.31-3.87, P?=?0.012) increased the risk of HFS. The association between the genotype GT of TYMS rs2606241 (OR?=?1.27, 95% CI 0.73-2.23, P?=?0.012) and HFS was uncertain. Further eQTL analyses confirmed that the alleles of rs3737964 and rs4846048 affected the gene expression levels of MTHFR in cis. CONCLUSIONS:We have identified four potentially useful pharmacogenetic markers, TYMS rs2606241, TYMS rs2853741, MTHFR rs3737964, and MTHFR rs4846048 to predict capecitabine-induced HFS in MBC patients.

Dataset Information

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

Publications

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

Similar Datasets

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