Abstract
Drug resistance, which is closely correlated with an imbalance in apoptosis, endows colorectal cancer (CRC) with enhanced progression capacity irrespective of the treatment with therapeutics. We report that miR-15b-5p is a tumor suppressor whose level is globally decreased in CRC cells and tissues. Over-expression of miR-15b-5p not only promoted 5-fluorouracil (5-FU)-induced cellular apoptosis but also reversed the chemoresistance of 5-FU in vitro and in vivo. As a key mediator of inflammation-induced cancer, miR-15b-5p enhances these therapeutic effects are mainly attributed to targeting of the NF-κB signaling pathway through negative regulation of NF-κB1 and one of its kinase complexes IKK-α. miR-15b-5p mediates NF-ĸB regulation by targeting the anti-apoptosis protein XIAP in vitro. Together, these results establish an axis of miR-15b-mediated apoptosis regulation, which reverses chemoresistance and suppresses CRC progression. These findings suggest that miR-15b-5p may be a potential agent for CRC treatment, particularly for 5-FU-resistant CRC.
Highlights
For over 50 years, 5-fluorouracil (5-FU) has been used as the first-line chemotherapeutic agent for colorectal cancer (CRC)[1]; the response rate of advanced CRC to 5-FU is only 10–15%2
The downregulation of miR-15b-5p in CRC patients’ tissues was further validated using data collected from different study groups in the Cancer Genome Atlas (TCGA) Data Portal (Fig. 1D)
In drug-resistant tumors, the most determinant property for miRNA efficacy against chemotherapy resistance is the ability of the miRNAs to induce cell apoptosis
Summary
For over 50 years, 5-fluorouracil (5-FU) has been used as the first-line chemotherapeutic agent for colorectal cancer (CRC)[1]; the response rate of advanced CRC to 5-FU is only 10–15%2. Not surprisingly, acquired resistance is more frequent during the course of anticancer drug treatment including chemotherapy and targeted therapies[5, 6]; many cancer patients who initially respond well to chemotherapy gradually exhibit decreased sensitivity to the specific chemotherapeutic. This acquired resistance may be attributed to long-term drug exposure, resulting in the development of mutations or adaptive processes; the mechanisms underlying such chemoresistance remain to be fully elucidated. The aim of this study was to assess the expression patterns of miR15b-5p in multiple CRC cell lines as well as in CRC tissues, and to investigate a potential correlation between miR-15b-5p and 5-FU chemosensitivity of CRC using two cell lines and animal models
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