Journal
ONCOTARGET
Volume 8, Issue 13, Pages 21719-21732Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.15559
Keywords
colorectal carcinoma; multidrug-resistance; miR-503-5p; PUMA; p53
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Funding
- National Natural Science Foundation of China [81503434, 81502540, 81473482]
- the twelfth five year key subject (Integrated Chinese and Western Medicine) of traditional Chinese medicine of State Administration of Traditional Chinese medicine
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The development of multidrug-resistance (MDR) is a major contributor to death in colorectal carcinoma (CRC). Here, we investigated the possible role of microRNA (miR)-503-5p in drug resistant CRC cells. Unbiased microRNA array screening revealed that miR-503-5p is up-regulated in two oxaliplatin (OXA)-resistant CRC cell lines. Overexpression of miR-503-5p conferred resistance to OXA-induced apoptosis and inhibition of tumor growth in vitro and in vivo through down-regulation of PUMA expression. miR-503-5p knockdown sensitized chemoresistant CRC cells to OXA. Our studies indicated that p53 suppresses miR-503-5p expression and that deletion of p53 upregulates miR-503-5p expression. Inhibition of miR-503-5p in p53 null cells increased their sensitivity to OXA treatment. Importantly, analysis of patient samples showed that expression of miR-503-5p negatively correlates with PUMA in CRC. These results indicate that a p53/miR-503-5p/PUMA signaling axis regulates the CRC response to chemotherapy, and suggest that miR-503-5p plays an important role in the development of MDR in CRC by modulating PUMA expression.
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