Induced miR‐31 by 5‐fluorouracil exposure contributes to the resistance in colorectal tumors

Abstract

Drug resistance makes treatment difficult in cancers. The present study identifies and analyzes drug resistance‐related miRNA in colorectal cancer. We established 4 types of 5‐fluorouracil (5‐FU)‐resistant colon cancer cell lines in vitro and in vivo. We then analyzed the miRNA expression profile by miRNA array in these 4 cell lines, and identified the drug resistance‐related miRNAs. We examined the expression levels of the identified miRNA in 112 colorectal tumor samples from the patients. We identified 12 possible miRNAs involved in 5‐FU resistance by miRNA arrays. We then examined the relationship between miR‐31, which was the most promising among them, and drug resistance. The ectopic expression of mimic miR‐31 showed significant 5‐FU resistance in the parental DLD‐1 cells, while anti–miR‐31 caused significant growth inhibition in DLD/F cells; that is, 5‐FU‐resistant colon cancer cell line DLD‐1 under exposure to 5‐FU. When we exposed high doses of 5‐FU to parent or 5‐FU‐resistant cells, the expression levels of miR‐31 were raised higher than those of controls. Notably, the expression levels of miR‐31 were positively correlated with the grade of clinical stages of colorectal tumors. The protein expression levels of factors inhibiting hypoxia‐inducible factor 1 were downregulated by transfection of mimic miR‐31 into DLD‐1 cells. This study provides evidence supporting the association of miR‐31 with 5‐FU drug resistance and clinical stages of colorectal tumors.

miR‑31 promotes tumorigenesis in ulcerative colitis‑associated neoplasia via downregulation of SATB2

“…In addition, the expression of miR-31 was elevated in 5-FU-resistant colon cancer cell lines. Of note, the miR-31 levels were indicated to be positively associated with the clinical stage of CRC (28). In addition, the relative expression of miR-31 was positively correlated with the survival time of the patients (29).…”

MicroRNA Profiling in Oesophageal Adenocarcinoma Cell Lines and Patient Serum Samples Reveals a Role for miR-451a in Radiation Resistance

“…miR-31-5p and miR-152-3p were associated with both in vitro 5-FU resistance and in vivo response to chemoradiotherapy that included 5-FU treatment. Both of these miRNAs have been associated with the response to 5-FU in colorectal cancer [ 58 , 59 , 60 ].…”

The Roles of Hypoxia-Inducible Factors and Non-Coding RNAs in Gastrointestinal Cancer

“…In addition, chemotherapy resistance is also associated with miRNA expression levels. In colorectal cancer, enhancing miR-31 expression using 5-FU, one of the most common anticancer drugs, can promote chemoresistance [78]. Since miR-31 directly suppresses FIH-1 expression [49], these studies suggest that HIF-1α is strongly involved in miR-31-mediated resistance.…”