Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell

Department of Transplantation and Hepatic Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai 200127, People's Republic of China.
Biochemical and Biophysical Research Communications (Impact Factor: 2.28). 06/2012; 423(4):826-31. DOI: 10.1016/j.bbrc.2012.06.048
Source: PubMed

ABSTRACT Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR-199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.

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    • "The majority of relevant preclinical studies using numerous chemotherapeutics including vorinostat, cyclophosphamide, and imatinib have demonstrated that autophagy significantly inhibits the efficacy of several classes of anticancer agents and helps to drive the acquired resistance [42] [43] [44]. Furthermore, accumulating evidence has indicated that autophagy is involved in adaptation of cancer cells to chemotherapy [45] [46]. These observations suggest that under chemotherapeutic treatments, autophagy is often activated as a cytoprotective mechanism for tumor cell to survive the effects of anticancer drugs which, in turn, may drive chemoresistance . "
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    • "For example, miRs-193a-3p and 146a suppress apoptosis via modulation of proapoptotic CASP2L through SRSF2, and SMAD4, respectively, whereas decreased miR- 199a-5p in resistant cells increases cell proliferation by activation of autophagy via ATG7. Importantly, in all three studies, the sensitivity to the respective chemotherapeutics could be altered in vitro by modulating miRNA abundance (Tomokuni et al., 2011; Ma et al., 2012; Xu et al., 2012). Ji et al. (2009) recently dissected the miRNA contribution for the response to adjuvant therapy with IFN␣ thereby confirming the therapeutic potential of miRNA-guided treatment modalities in HCC. "
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    • "17. Li J, Kanekiyo T, Shinohara M, Zhang Y, LaDu MJ, Xu H et al (2012) Differential regulation of amyloid-beta endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms. J Biol Chem 287(53):44593–44601. doi:10.1074/jbc.M112.420224 "
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