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.
"One important question to address further is whether or not changes in miR-199a/b-5p endogenous levels influence endocytosis. The documented observation that in most of cancers miR-199a-5p expression is downregulated supports the idea that cancer cells can exploit this fact to ensure the intracellular trafficking necessary for growth, therefore enabling cancer progression (Ramsay et al., 2007; Xu et al., 2012). Intriguingly, miR-199a-5p overexpression inhibits tumor cell migration without affecting cellular proliferation and viability (Cheung et al., 2011; Duan et al., 2011). "
"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   . Furthermore, accumulating evidence has indicated that autophagy is involved in adaptation of cancer cells to chemotherapy  . 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 . "
"Cisplatin treatment also results in decreased
miR-199a-5p levels in human HCC cell lines. miR-199a-5p/autophagy signaling
represents a novel pathway that regulates chemoresistance and thus offers a new
target for the cisplatin-based chemotherapy of HCC []. "
[Show abstract][Hide abstract] ABSTRACT: The pathogenesis of hepatocellular carcinoma (HCC) is not fully understood, which has affected the early diagnosis and treatment of HCC and the survival time of patients. MicroRNAs (miRNAs) are a class of evolutionarily conserved small, non-coding RNAs, which regulate the expression of various genes post-transcriptionally. Emerging evidence indicates that the key enzymes involved in the miRNA biosynthesis pathway and some tumor-specific miRNAs are widely deregulated or upregulated in HCC and closely associated with the occurrence and development of various cancers, including HCC. Early studies have shown that miRNAs have critical roles in HCC progression by targeting many critical protein-coding genes, thereby contributing to the promotion of cell proliferation; the avoidance of apoptosis, inducing via angiogenesis; and the activation of invasion and metastasis pathways. Experimental data indicate that discovery of increasing numbers of aberrantly expressed miRNAs has opened up a new field for investigating the molecular mechanism of HCC progression. In this review, we describe the current knowledge about the roles and validated targets of miRNAs in the above pathways that are known to be hallmarks of HCC, and we also describe the influence of genetic variations in miRNA biosynthesis and genes.
Cell Communication and Signaling 07/2014; 12(1):45. DOI:10.1186/PREACCEPT-5069088841256961 · 3.38 Impact Factor
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