Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell
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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ABSTRACT: Although the combination of etoposide (VP16) and cisplatin (DDP) is widely used as a first-line treatment for advanced-stage small-cell lung cancer (SCLC), chemoresistance limits its clinical use. Abnormalities of autophagy are associated with tumor chemoresistance. The present study found that miR-24-3p, a recently discovered microRNA, is significantly downregulated in VP16-DDP-resistant SCLC cells (H446/EP) compared with VP16-DDP-sensitive parent cells (H446). Forced expression of miR-24-3p sensitized H446/EP cells to VP16-DDP treatment because of a blockade of autophagic activity. We further found that downregulated miR-24-3p enhanced autophagy activation as it directly targets and inhibits autophagy-associated gene 4A (ATG4A). Overexpression of miR-24-3p into H446/EP cells led to reduction of the ATG4A protein level, allowing SCLC cells to resensitize to VP16-DDP. We conclude that miR-24-3p regulates autophagy by targeting ATG4A. Inhibition of autophagy by increasing miR-24-3p could be the basis of a strategy to prevent and treat SCLC with combination chemotherapy, particularly in chemoresistant disease.Oncotarget 11/2014; · 6.63 Impact Factor
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ABSTRACT: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Protoporphyrin IX (PPIX) has been used for photodynamic therapy. Mesenchymal cancer cells adapt to tumor microenvironments for growth and metastasis possibly in association with miRNA dysregulation. In view of the effect of PPIX on cancer-related genes, and its potential to inhibit tumor growth and migration/invasion, this study investigated whether PPIX enables mesenchymal liver tumor to restore dysregulated miRNAs, and if so, whether it sensitizes the cancer cells to chemotherapy. In addition, we explored new target(s) of the miRNA(s) that contribute to the anti-cancer effects. Of the ten miRNAs predicted by the 3'-UTR of HIF-1α mRNA, PPIX treatment increased miR-199a-5p, leading to the inhibition of E2F3 expression which is upregulated in mesenchymal liver tumor. miR-199a-5p levels were downregulated in HCC with E2F3 overexpression. An approach modulating epithelial-mesenchymal transition provided the expected changes in miR-199a-5p and E2F3 in vivo. PPIX prevented tumor cell growth and migration/invasion, and had a synergistic anti-cancer effect when combined with chemotherapeutics. In a xenograft model, PPIX treatment decreased overall growth and average tumor volume, which paralleled E2F3 inhibition. Overall, PPIX inhibited growth advantage and migratory ability of cancer cells and sensitized mesenchymal liver tumor cells to chemotherapeutics.Oncotarget 01/2015; · 6.63 Impact Factor
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ABSTRACT: Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.Seminars in Cancer Biology 03/2015; ePub ahead of print. DOI:10.1016/j.semcancer.2015.03.001 · 9.14 Impact Factor