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.
Keywords: 5-fluorouracil (5-FU), ABCF1, chemoresistance, CRCs, microsatellite instability, miRNA.
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