Abstract
MiRNAs may promote or inhibit tumor recurrence and drug resistance. MiR-139-5p is reportedly downregulated in colorectal cancer patient samples, but it is unknown whether and how miR-139-5p regulates drug resistance. Cancer stem cells (CSCs) are postulated to be important promoters of multiple drug resistance (MDR). In this study, we established a MDR cell model which strongly expressed the CSC-associated biomarkers CD44 and CD133. MiR-139-5p expression was reduced in MDR cell lines, while overexpression of miR-139-5p reversed CD44+/CD133+-associated MDR. We also identified NOTCH1, an important protein for stem cell maintenance and function, as a direct target of miR-139-5p, both in vitro and in a knockout mouse model. Notch1 expression was upregulated in tumor samples and inversely correlated with expression of miR-139-5p. Silencing NOTCH1 exerted an effect similar to overexpression of miR-139-5p by inhibiting the CD44+ and CD133+ population and reversing the drug-resistant phenotype. In conclusion, miR-139-5p downregulated NOTCH1 signaling to reverse CD44+/CD133+-associated MDR in colorectal cancer cells. Given this insight into the miRNA regulation of MDR, miR-139-5p could be a promising therapeutic target for colorectal cancer therapy.
Highlights
Colorectal cancer (CRC) is the third most common cause of cancer-related death, but treatment of CRC often fails to eradicate all of the tumor cells because the cells have intrinsic or acquired drug resistance [1, 2]
An in vivo study demonstrated that overexpression of NOTCH1 ablated the inhibitory effects of miR-139-5p on tumor growth (Figure 6D). All these results provided further evidence that NOTCH1 expression is inhibited by miR-139-5p, and that the downregulation of miR-139-5p is a key promoter of CD44+/CD133+-associated colorectal drug resistance because it potentiates NOTCH1 expression
In many cases of tumor recurrence, the cancer cells are resistant to conventional chemotherapy
Summary
Colorectal cancer (CRC) is the third most common cause of cancer-related death, but treatment of CRC often fails to eradicate all of the tumor cells because the cells have intrinsic or acquired drug resistance [1, 2]. Understanding the mechanism of MDR in CRC cells is crucial for the optimization of current therapeutic techniques. CSCs can be defined by their high expression of CD44 [10] and CD133, and this unique phenotype allows the identification of colorectal CSCs as a distinct population from the bulk tumor cells. This CD44+/ CD133+ cell population is thought to initiate and sustain tumor growth, and is an obvious target for therapeutic treatment [11]. The CD133+/CD44+ population, which comprises the cancer initiating cells (CICs) [12], may be the best biomarker for the early detection of CRC [13,14,15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
