Edited by Tamas DalmayKeywords: MiR-199a-5p DRAM1 Beclin1 Autophagy Irradiation a b s t r a c t 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.

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.

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The evidence of this study suggests that a combinatorial approach that inhibits both the MAPK and PI3K/AKT/mTOR pathways exerts a greater antitumor effect than sorafenib alone in thyroid cancer cell lines.

The multi-target kinase inhibitor sorafenib has been approved for the treatment of patients with advanced differentiated thyroid cancer. However, different sensitivities to sorafenib have been observed, and few patients have benefited from sorafenib treatment in the long term. In the event of acquired resistance to sorafenib it is not beneficial to continue treatment in most patients. Autophagy can be induced in a variety of cancer treatments and plays an important role in cancer treatment. The role of autophagy in sorafenib treatment of thyroid cancer has not been fully demonstrated. The present study investigated whether autophagy is activated by sorafenib during the treatment of thyroid cancer, examined the underlying mechanisms, and explored potential strategies to enhance the therapeutic sensitivity of sorafenib. Chloroquine (CQ) is an autophagy inhibitor that has been reported to increase sensitivity to various cancer treatments. Thyroid cancer xenograft model mice were treated with sorafenib, CQ, or a combination of sorafenib and CQ. We observed that CQ or sorafenib treatment suppressed tumor growth, while mice treated with the combination of sorafenib and CQ displayed significantly reduced tumor growth compared with those treated with sorafenib or CQ alone. Western blotting results indicated that sorafenib concurrently inhibited the activities of the MAPK and AKT/mTOR pathways in thyroid cancer. Autophagy was activated by sorafenib in thyroid cancer, both in vitro and in vivo, which was at least in part due to suppression of the AKT/mTOR pathway. Combination treatment including CQ could inhibit the autophagic flux induced by sorafenib. Silencing the key autophagy gene ATG5 using small interfering RNA also increased the anticancer effect of sorafenib. In summary, the present study revealed that inhibition of autophagy enhances the anticancer effect of sorafenib, and the combination of CQ with sorafenib treatment represents a potential therapeutic strategy for treating advanced differentiated thyroid cancer.

Abstract. The sharply increasing incidence of thyroid cancer has attracted considerable attention over the last few years. The combination of surgery, radioiodine ablation and thyroid-stimulating hormone suppression is usually efficient for the majority of thyroid tumors. However, advanced thyroid cancer that is recurrent, metastatic and 131 I-refractory, or medullary thyroid cancer, pose a therapeutic challenge. Autophagy is a process that metabolizes damaged cytoplasmic organelles and long-lived proteins in order to recycle cellular materials and maintain homeostasis. It has been confirmed that autophagy plays a dual role during cancer development, progression and treatment, mainly depending on the type and stage of the tumor. Autophagy modulation has become a potential therapeutic target for diverse diseases. The mechanism of thyroid tumorigenesis and cancer progression was largely demonstrated to be correlated with the dysregulation of the Ras/Raf/mitogenactivated protein kinase kinase̸extracellular signal-regulated kinase and the phosphoinositide 3-kinase̸Akt̸mammalian target of rapamycin pathways, as well as with abnormal epigenetic modifications. Those mechanisms are associated with autophagy regulation and may be beneficial for the treatment of advanced thyroid cancer. However, the number of available studies on the role of autophagy in thyroid cancer development, progression and treatment outcome, is currently limited. The aim of this review was to elaborate on the relevant knowledge and future prospectives of autophagy in the treatment of thyroid cancer.