Abstract
BackgroundDespite advances in the development of efficient chemotherapy, the treatment of colorectal cancer (CRC) remains a challenge due to acquired chemoresistance. It has been reported that microRNAs (miRNAs) dysregulation is associated with the development of chemoresistance. Recently, the expression of miR-199b-3p has been found to be significantly different between cetuximab (CTx)-resistant and -sensitive CRC cells. However, its role and the underlying mechanisms in acquired chemoresistance to CTx in CRC are still obscure.MethodsHere we report that miR-199b-3p is significantly up-regulated in both CTx-resistant (CTxR) CRC tissues and cell lines.ResultsFunctional assays showed that suppressing miR-199b-3p could improve the sensitivity of CRC-CTxR cells to CTx, thereby reducing cell proliferation, migration and invasion, and enhancing cell apoptosis. Mechanistic studies revealed that CRIM1 is a direct target of miR-199b-3p in CRC-CTxR cells; and the effect of miR-199b-3p on CTx-resistance was exerted by regulating the Wnt/β-catenin signaling pathway via CRIM1. Furthermore, mice xenograft models were established and confirmed that down-regulating miR-199b-3p restores the inhibition effect of CTx on tumor growth in CRC-CTxR. Collectively, our data suggest that silencing miR-199b-3p could enhance the anti-tumor effects of CTx on CTx-resistant CRC in vitro and in vivo by activating Wnt/β-catenin signaling via the down-regulation of CRIM1.ConclusionsOur findings suggest miR-199b-3p might serve as a promising therapeutic target against CTx resistant CRC, and provide scientific information for exploring novel strategies of improving the efficacy of CTx for CRC patients.
Highlights
Despite advances in the development of efficient chemotherapy, the treatment of colorectal cancer (CRC) remains a challenge due to acquired chemoresistance
Results miR‐199b‐3p expression is positively associated with acquired resistance to CTx in CRCInitially, Quantitative real-time PCR (qRT-PCR) detecting the expression levels of miR199b-3p in the CRC tissues showed that miR-199b-3p is significantly up-regulated in CTx-non-responders compared with CTx-responders (Fig. 1A)
Differential expressions of miR-199b-3p, which may be associated with chemoresistance, were detected in CRC-CTxR cell lines compared with parental sensitive ones (Fig. 1B)
Summary
Despite advances in the development of efficient chemotherapy, the treatment of colorectal cancer (CRC) remains a challenge due to acquired chemoresistance. The expression of miR-199b-3p has been found to be significantly different between cetuximab (CTx)-resistant and -sensitive CRC cells. MiR-302a regulates the expression of both NFIB and CD44 to suppress metastasis and CTx resistance in CRC [11]. Mussnich et al [14] identified both miR-199a-5p and miR-199b-3p as significant differentially expressed miRNAs between CTxsensitive and CTx-resistant CRC cells. They further demonstrated that miR-199a-5p contributed to acquired resistance to CTx in CRC cells by conducting functional analyses. While the expression of miR-199b-3p is functionally involved in acquired resistance to CTx in CRC has not been reported yet
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