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

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...

Full description

Saved in:
Bibliographic Details
Published in:Cancer science 2019-08, Vol.110 (8), p.2540-2548
Main Authors: Nakagawa, Yoshihito, Kuranaga, Yuki, Tahara, Tomomitsu, Yamashita, Hiromi, Shibata, Tomoyuki, Nagasaka, Mitsuo, Funasaka, Kohei, Ohmiya, Naoki, Akao, Yukihiro
Format: Article
Language:English
Subjects:
5-Fluorouracil
Antimetabolites, Antineoplastic - pharmacology
Cancer therapies
Cell cycle
Cell Line, Tumor
Colon cancer
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
Down-Regulation - drug effects
Down-Regulation - genetics
Drug dosages
Drug resistance
Drug Resistance, Neoplasm - genetics
Ectopic expression
Experiments
Fluorouracil - pharmacology
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Gene Expression Regulation, Neoplastic - genetics
Humans
Hypoxia
microRNA
MicroRNAs
MicroRNAs - genetics
miRNA
Original
Proteins
Transfection
Transfection - methods
Tumor cell lines
Tumors
Warburg effect
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. 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.
ISSN:1347-9032
1349-7006
DOI:10.1111/cas.14090