Induced miR‐31 by 5‐fluorouracil exposure contributes to the resistance in colorectal tumors. Issue 8 (23rd July 2019)

• Record Type: Journal Article
• Authors: Nakagawa, Yoshihito; Kuranaga, Yuki; Tahara, Tomomitsu; Yamashita, Hiromi; Shibata, Tomoyuki; Nagasaka, Mitsuo; Funasaka, Kohei; Ohmiya, Naoki; Akao, Yukihiro
• Is Part Of: Cancer science. Volume 110:Issue 8(2019)
• Page Start: 2540
• Page End: 2548
• Publication Date: 2019-07-23
• Subjects: 5‐fluorouracil -- colorectal cancer -- drug resistance -- microRNA -- Warburg effect; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.14090
• Languages: English
• ISSNs: 1347-9032

Abstract

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. Abstract : In this study, we mainly analyzed the relationship between 5‐FU resistance and the miRNA profile of colorectal tumors. Moreover, the expression level of miR‐31 was higher in carcinomas invading submucosa and advanced cancer than in carcinomas in situ and adenomas. These data might suggest that the increased expression level of miR‐31 caused 5‐FU resistance in colorectal cancer through maintenance of the Warburg effect.