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.

• Authors: Yoshihito Nakagawa, Yuki Kuranaga, Tomomitsu Tahara, Hiromi Yamashita, Tomoyuki Shibata, Mitsuo Nagasaka, Kohei Funasaka, Naoki Ohmiya, Yukihiro Akao
• Journal: Cancer science (Cancer Sci) Vol. 110 Issue 8 Pg. 2540-2548 (Aug 2019) ISSN: 1349-7006 [Electronic] England
• PMID: 31162779 (Publication Type: Journal Article)
• Copyright: © 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antimetabolites, Antineoplastic
• MIRN31 microRNA, human
• MicroRNAs
• Fluorouracil

Topics

• Antimetabolites, Antineoplastic (pharmacology)
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, genetics)
• Down-Regulation (drug effects, genetics)
• Drug Resistance, Neoplasm (genetics)
• Fluorouracil (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Humans
• MicroRNAs (genetics)
• Transfection (methods)