miR-34a Regulates Multidrug Resistance via Positively Modulating OAZ2 Signaling in Colon Cancer Cells
Although aberrant expression of miR-34a, an essential tumor suppressor miRNA, has been frequently observed in colon cancer (CCa), whether miR-34a can regulate CCa progression by modulating other facets of this malignancy (such as multidrug resistance, MDR) remains unknown. Here, we report for the fi...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2018-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2018/7498514 |
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| Summary: | Although aberrant expression of miR-34a, an essential tumor suppressor miRNA, has been frequently observed in colon cancer (CCa), whether miR-34a can regulate CCa progression by modulating other facets of this malignancy (such as multidrug resistance, MDR) remains unknown. Here, we report for the first time that miR-34a expression was significantly downregulated in clinical CCa samples from oxaliplatin-resistant patients and in experimentally established multidrug-resistant CCa cells. By using histoculture drug response assay, we further confirmed that clinical CCa samples with lower miR-34a expression appeared to be more resistant to chemotherapy. Functionally, ectopic expression of exogenous miR-34a resensitized multidrug-resistant HCT-8/OR cells to oxaliplatin treatment, whereas miR-34a inhibition augmented the oxaliplatin resistance in chemosensitive HCT-8 cells. Mechanistically, miR-34a positively regulated the mRNA stability of the ornithine decarboxylase antizyme 2 (OAZ2) by directly targeting its three prime untranslated region (3′UTR). Consequently, suppression of the expression of miR-34a/OAZ2 signaling by chemotherapeutic agents significantly enhanced the activation of MDR-associated ATP-binding cassette (ABC) transporters and antiapoptosis pathways, thus leading to MDR development in CCa cells. Collectively, our combined analysis reveals a critical role of miR-34a/OAZ2 cascade in conferring a proper cellular response to CCa chemotherapy. |
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| ISSN: | 2314-8861 2314-7156 |