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ABSTRACT: Autophagy is a self-degrading process that is triggered by diverse stimuli including ionizing radiation. In this study we show novel phenomena in which transfection of miR-199a-5p mimic significantly suppresses IR-induced autophagy in MCF7 cells, and up-regulates basal and IR-induced autophagy in MDA-MB-231 breast cancer cells. We also identify DRAM1 and Beclin1 as novel target genes for miR-199a-5p. Overexpression of miR-199a-5p inhibits DRAM1 and Beclin1 expression in MCF7 cells, while it enhances expression of these genes in MDA-MB-231 cells. Furthermore, we show that miR-199a-5p sensitizes MDA-MB-231 cells to irradiation. Therefore, our data identify miR-199a-5p as a novel and unique regulator of autophagy, which plays an important role in cancer biology and cancer therapy.
FEBS letters 01/2013; · 3.54 Impact Factor
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ABSTRACT: Autophagy is an evolutionarily conserved, multi-step lysosomal degradation process in which a cell degrades its own long-lived proteins and damaged organelles. Ataxia telangiectasia mutated (ATM) has recently been shown to upregulate the process of autophagy. Previous studies showed that certain microRNAs, including miR-18a, potentially regulate ATM in cancer cells. However, the mechanisms behind the modulation of ATM by miR-18a remain to be elucidated in colon cancer cells. In the present study, we explored the impact of miR-18a on the autophagy process and ATM expression in HCT116 colon cancer cells. To determine whether a preliminary link exists between autophagy and miR-18a, HCT116 cells were irradiated and quantitative (q) PCR was performed to measure miR-18a expression. HCT116 cells were transfected with an miR-18a mimic to study its impact on indicators of autophagy. Western blotting and luciferase assays were implemented to explore the impact of miR-18a on ATM gene expression in HCT116 cells. The results showed that miR-18a expression was strongly stimulated by radiation. Ectopic overexpression of miR-18a in HCT116 cell lines potently enhanced autophagy and ionizing radiation-induced autophagy. Moreover, miR-18a overexpression led to the upregulation of ATM expression and suppression of mTORC1 activity. Results of the present study pertaining to the role of miR-18a in regulating autophagy and ATM gene expression in colon cancer cells revealed a novel function for miR-18a in a critical cellular event and on a crucial gene with significant impacts in cancer development, progression, treatment and in other diseases.
Molecular Medicine Reports 12/2012; · 0.42 Impact Factor
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ABSTRACT: Multidrug resistance (MDR) has become an obstacle for chemotherapy of cancer. p53 is reported to participate in the regulation of MDR, but the association between p53 status and MDR are complicated and conditional. It has been verified that apoptosis is not the only mechanism for MDR regulation by p53, the roles of autophagy in MDR is less studied.
Human ovarian carcinoma cell lines SKOV3 and multidrug resistant phenotype SKVCR cells were used and wild-type p53 (wt p53) and mutant 175H constructs were introduced into cells to establish cell models with different p53 status by gene engineering, the sensitivity to vincristine (VCR), cisplatin (DDP), pirarubicin (THP) and etoposide (VP-16) were detected by MTT assay, Western blot and quantitative real-time PCR were used to detect the expression of protein and mRNA, especially, monodansylcadaverine (MDC) staining was used for autophagy rate, Hoechst 33342/propidium iodide (PI) were used to assess apoptosis and necrosis.
SKVCR cells induced by VCR shown overexpression of P-glycoprotein (P-gp) and MDR, and also displayed an enhanced autophagy compared with parental SKOV3. Wt p53 and 175H has no influence on drug sensitivity in SKOV3, while both sensitized SKVCR cells to VCR, THP and VP-16, especially 175H. The introduction of wt p53-induced apoptosis only, while 175H trigged autophagic cell death, necrosis and apoptosis so as to reverse the MDR.
The enhancement of autophagy in MDR cells allows to survive during chemotherapy stress, autophagy plays important role in wt p53 and mutant p53-immediated MDR. The different influence of p53 status on drug sensitivity hint the individual treatment strategies based on p53 status in patients.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 02/2012; 66(4):271-8. · 2.24 Impact Factor
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ABSTRACT: Hepatocellular carcinoma (HCC), the 5th most common cancer and the third most common cause of cancer-related death in the world with an estimated incidence of approximately 1 million new cases annually, has becoming a major global health problem in the world. A variety of treatment modalities, including resection, liver transplantation, transarterial chemoembolization (TACE), local ablative therapy and radiation therapy (RT) have been reported. Although partial hepatectomy and liver transplantation may offer the best chance of cure, only 15% of the patients have the chance to be treated by surgery when diagnosed. The effectiveness of systemic chemotherapy for HCC has been minimal, and local ablative therapy may offer comparable survival in patients with small HCC and preserve liver function. Recently, with developments in radiotherapy techniques, radiotherapy has been shown to play potential roles in a wide spectrum of HCC and to become more important so that it is necessary to evaluate the effect of radiotherapy in treatment of HCC. This paper is aiming mainly at the current radiation therapy strategies and their current advances, the optimal radiation therapy strategies will complement the current treatments and improve the treatment efficiency.
Cancer treatment reviews 04/2010; 36(2):157-63. · 5.30 Impact Factor
