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      Circular RNA circEPSTI1 accelerates cervical cancer progression via miR-375/409-3P/515-5p-SLC7A11 axis

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          Abstract

          Background: Circular RNAs (circRNAs) is one kind of non-coding RNAs (ncRNAs) and exert crucial functions in biological processes and intracellular gene expression modulation. However, the biological roles and expression status of the majority of circRNAs still remain unknown in cervical cancer.

          Results: In this study, circEPSTI1 (hsa_circRNA_000479) was significantly upregulated in cervical cancer. We first discovered the impact of circRNA on cell ferroptosis in cervical cancer. Interestingly, circEPSTI1 attenuates the effect of ferritin which is mediated by SLC7A11 based on lipid peroxidation measurements and reduced glutathione and glutathione (GSH/GSSG) assay.

          Conclusions: circEPSTI1-miR-375/409-3P/515-5p-SLC7A11 axis affected the proliferation of cervical cancer via the competing endogenous RNAs (ceRNA) mechanism and was relative to ferroptosis. Our findings provided experimental evidences which revealed that circEPSTI1 might act as a new and useful biomarker for monitoring and treatment target for cervical cancer.

          Methods: The expression of circEPSTI1 was examined in cervical cancer cells. Then, we observed the impact of circEPSTI1 expression on the proliferation of cervical cancer by loss-of-function assays both in vivo and vitro. RIP and luciferase reporter assay revealed that circEPSTI1 sponges miR-375, miR-409-3p and miR-515-5p to upregulate SLC7A11 expression. We applied mouse xenograft experiments in mice to validate our results.

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          Most cited references34

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          Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

          This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.
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            Ferroptosis: an iron-dependent form of nonapoptotic cell death.

            Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

              Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
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                Author and article information

                Journal
                Aging (Albany NY)
                Aging
                Aging (Albany NY)
                Impact Journals
                1945-4589
                15 February 2021
                02 February 2021
                : 13
                : 3
                : 4663-4673
                Affiliations
                [1 ]Department of Critical Care Medicine, Hengyang Maternal and Child Health Hospital, Hengyang 421001, Hunan Province, China
                [2 ]Yueyang Maternal and Child Health Hospital, Yueyang 414000, Hunan Province, China
                [3 ]Innovative Practice Base for Postgraduate Training of Basic Medicine and Clinical Collaboration, University of South China and Yueyang Maternal and Child Health Hospital, Yueyang 414000, Hunan Province, China
                [4 ]Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China
                [5 ]Department of Gynecology, The Third Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
                Author notes
                Correspondence to: Zhiwei Zhang; email: nhdxzzw@usc.edu.cn
                Correspondence to: Shuijing Yi; email: yishuijing@csu.edu.cn
                Article
                202518 202518
                10.18632/aging.202518
                7906137
                33534779
                8da30e19-91bd-460a-9386-644bb5e4bd71
                Copyright: © 2021 Wu et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 08 July 2020
                : 25 December 2020
                Categories
                Research Paper

                Cell biology
                cervical cancer,circepsti1,circular rnas,mir-375,slc7a11
                Cell biology
                cervical cancer, circepsti1, circular rnas, mir-375, slc7a11

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