Elevated microRNA-23a Expression Enhances the Chemoresistance of Colorectal Cancer Cells with Microsatellite Instability to 5-Fluorouracil by Directly Targeting ABCF1.
Colorectal cancer (CRC) is one of the most common tumor types worldwide. A frequent subtype of CRC is defined by a deficiency in the mismatch repair (MMR) pathway, constantly found in combination with microsatellite instability (MSI), which not only contributes to the pathogenesis of a large proportion of CRC, but also controls the response to multiple drugs used to treat CRCs. The most commonly used chemotherapeutic agent for CRC is 5-fluorouracil (5-FU). However, CRC with MSI frequently acquires 5-FU resistance, and the exact mechanism underlying how CRC cells acquire chemoresistance to 5-FU remains incompletely understood. Recently, emerging evidence has demonstrated that microRNAs (miRNAs) are key players in multidrug resistance. In this study, we aimed to characterize the expression profiles and functions of miRNAs in 5-FU-resistant CRC with MSI. We found that miR-23a was significantly elevated in MSI CRC cells and tissues compared to microsatellite stability (MSS) CRC cells and tissues. Ectopic expression of miR-23a increased the viability and survival of MSS CRC cells. Inversely, downregulation of miR-23a reduced viability in and promoted cell apoptosis in MSI CRC cells treated with 5-FU. Moreover, we demonstrated that ABCF1 is a direct target of miR-23a. Additionally, the expression of miR-23a was inversely correlated with the expression of ABCF1 in CRC tissues. Interestingly, repressing ABCF1 expression by either miR-23a overexpression or siABCF1 led to recovery of 5-FU sensitivity in MSI CRC cells. These data demonstrated that miR-23a enhances 5-FU resistance in MSI CRC cells through targeting ABCF1 and thus provided important implications for therapeutic approaches aiming to overcome MSI CRC resistance to 5-FU.
Xiang
X
Li
Xiaolei
X
Li
Daixiang
D
Liao
Xiaohui
X
Wang
Zhiqiang
Z
Wu
Jing
J
Nie
Miaomiao
M
Bai
Xiaobing
X
Fu
Qian
Q
Mei
Department of Molecular Biology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing 100853, China. hanwdrsw69@yahoo.com.
Weidong
W
Han
D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D053842:Microsatellite Instability / Q000187:drug effects*
C115776:ABCF1 protein, human; D018528:ATP-Binding Cassette Transporters; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D005472:Fluorouracil