Abstract
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.
Highlights
Colon cancer (CCa) is one of the most frequently diagnosed malignancies and one of the leading causes of cancer-related mortality worldwide [1]
Despite the recent advances in the cancer treatment for advanced CCa, multidrug resistance (MDR) that occurs through unidentified mechanisms remains the major challenge for chemotherapy
MiR-34a was initially identified as a tumor suppressor miRNA, so its downregulation has been frequently observed in many malignancies including pancreatic cancer [28], squamous cell carcinoma [29], endometrial cancer [30], osteosarcoma [31], and hepatocellular carcinoma [32]
Summary
Colon cancer (CCa) is one of the most frequently diagnosed malignancies and one of the leading causes of cancer-related mortality worldwide [1]. A growing body of evidence suggests that deregulation of miRNA expression and function plays a key role in the development of drug resistance [9,10,11]. Two research groups have reported independently that augmentation of miR-34a expression could resensitize CCa cells to 5-fluorouracil-based chemotherapy [18, 19], pointing to an essential involvement of this important tumor suppressor miRNA in the metabolism of chemotherapeutic agents. In this regard, the current study was designed to further investigate whether miR-34a plays a potential role in the pathogenesis of CCa MDR.
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