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      OncoTargets and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the pathological basis of cancers, potential targets for therapy and treatment protocols to improve the management of cancer patients. Publishing high-quality, original research on molecular aspects of cancer, including the molecular diagnosis, since 2008. Sign up for email alerts here. 50,877 Monthly downloads/views I 4.345 Impact Factor I 7.0 CiteScore I 0.81 Source Normalized Impact per Paper (SNIP) I 0.811 Scimago Journal & Country Rank (SJR)

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      Silencing Snail Reverses Epithelial-Mesenchymal Transition and Increases Radiosensitivity in Hypopharyngeal Carcinoma

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          Abstract

          Purpose

          Radioresistance in response to radiotherapy leads to cancer recurrence and poor survival in hypopharyngeal carcinoma patients. Previous studies indicate that ionizing radiation (IR) can induce epithelial–mesenchymal transition (EMT) that promotes the radioresistance, migration and invasiveness of tumors. The aim of this study was to explore the role of Snail in EMT and acquired radioresistance in hypopharyngeal carcinoma.

          Methods

          Radioresistance human hypopharyngeal carcinoma cells (FaduRR) were previously established from the Fadu cell line. Radiosensitivity was measured by colony forming assay. Western blot and Quantitative real-time PCR were used to detect the expression of EMT phenotypes and AKT/GSK-3β/Snail signaling pathway related proteins in Fadu+4Gy and FaduRR cells. Transwell and wound-healing assays were used to measure cell migration and invasiveness. EMT-related proteins and Snail expression were assessed in 80 hypopharyngeal carcinoma patient samples from radiosensitive and radioresistance groups using immunohistochemistry. Snail was silenced to evaluate its effects on EMT, radioresistance, migration, and invasiveness of FaduRR cells.

          Results

          The molecular characteristics of EMT were observed following radiation treatment, with migration, invasiveness and radioresistance enhanced in Fadu+4Gy and FaduRR cells. Moreover, we demonstrated that IR-induced EMT by activating the AKT/GSK-3β/Snail signaling pathway and that Snail silencing reversed EMT and attenuated radioresistance in FaduRR cells. Significant differences in EMT-related proteins and Snail expression were observed between radiosensitive and resistant group.

          Conclusion

          We demonstrate that IR can trigger EMT and enhance the migration, invasiveness, and radioresistance of FaduRR cells through the AKT/GSK-3β/Snail axis. Snail silencing could attenuate these effects and represents a novel therapeutic target for EMT-induced radioresistance in hypopharyngeal carcinoma.

          Most cited references25

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          Epithelial-mesenchymal transitions in development and disease.

          Jean Paul Thiery, Hervé Acloque, Ruby Y J Huang … (2009)
          The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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            Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer cells by ionizing radiation

            Su-Yeon Lee, Eui-Kyong Jeong, Min Kyung Ju … (2017)
            Radiation therapy is one of the major tools of cancer treatment, and is widely used for a variety of malignant tumours. Radiotherapy causes DNA damage directly by ionization or indirectly via the generation of reactive oxygen species (ROS), thereby destroying cancer cells. However, ionizing radiation (IR) paradoxically promotes metastasis and invasion of cancer cells by inducing the epithelial-mesenchymal transition (EMT). Metastasis is a major obstacle to successful cancer therapy, and is closely linked to the rates of morbidity and mortality of many cancers. ROS have been shown to play important roles in mediating the biological effects of IR. ROS have been implicated in IR-induced EMT, via activation of several EMT transcription factors—including Snail, HIF-1, ZEB1, and STAT3—that are activated by signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, G-CSF, EGFR/PI3K/Akt, and MAPK. Cancer cells that undergo EMT have been shown to acquire stemness and undergo metabolic changes, although these points are debated. IR is known to induce cancer stem cell (CSC) properties, including dedifferentiation and self-renewal, and to promote oncogenic metabolism by activating these EMT-inducing pathways. Much accumulated evidence has shown that metabolic alterations in cancer cells are closely associated with the EMT and CSC phenotypes; specifically, the IR-induced oncogenic metabolism seems to be required for acquisition of the EMT and CSC phenotypes. IR can also elicit various changes in the tumour microenvironment (TME) that may affect invasion and metastasis. EMT, CSC, and oncogenic metabolism are involved in radioresistance; targeting them may improve the efficacy of radiotherapy, preventing tumour recurrence and metastasis. This study focuses on the molecular mechanisms of IR-induced EMT, CSCs, oncogenic metabolism, and alterations in the TME. We discuss how IR-induced EMT/CSC/oncogenic metabolism may promote resistance to radiotherapy; we also review efforts to develop therapeutic approaches to eliminate these IR-induced adverse effects.
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              Epithelial–Mesenchymal Transition (EMT) Induced by TNF-α Requires AKT/GSK-3β-Mediated Stabilization of Snail in Colorectal Cancer

              Hao-Hao Wang, Hong-Sheng Wang, Bin-Hua Zhou … (2013)
              Chronic inflammation-promoted metastasis has been considered as a major challenge in cancer therapy. Pro-inflammatory cytokine TNFα can induce cancer invasion and metastasis associated with epithelial–mesenchymal transition (EMT). However, the underlying mechanisms are not entirely clear. In this study, we showed that TNFα induces EMT in human HCT116 cells and thereby promotes colorectal cancer (CRC) invasion and metastasis. TNFα-induced EMT was characterized by acquiring mesenchymal spindle-like morphology and increasing the expression of N-cadherin and fibronectin with a concomitant decrease of E-cadherin and Zona occludin-1(ZO-1). TNFα treatment also increased the expression of transcription factor Snail, but not Slug, ZEB1 and Twist. Overexpression of Snail induced a switch from E-cadherin to N-cadherin expression in HCT116 cells, which is a characteristic of EMT. Conversely, knockdown of Snail significantly attenuated TNFα-induced EMT in HCT116 cells, suggesting that Snail plays a crucial role in TNFα-induced EMT. Interestingly, exposure to TNFα rapidly increased Snail protein expression and Snail nuclear localization but not mRNA level upregulation. Finally, we demonstrated that TNFα elevated Snail stability by activating AKT pathway and subsequently repressing GSK-3β activity and decreasing the association of Snail with GSK-3β. Knockdown of GSK-3β further verified our finding. Taken together, these results revealed that AKT/GSK-3β-mediated stabilization of Snail is required for TNFα-induced EMT in CRC cells. Our study provides a better understanding of inflammation-induced CRC metastasis.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Onco Targets Ther
                Journal ID (iso-abbrev): Onco Targets Ther
                Journal ID (publisher-id): OTT
                Journal ID (pmc): ott
                Title: OncoTargets and therapy
                Publisher: Dove
                ISSN (Electronic): 1178-6930
                Publication date (Electronic): 16 January 2020
                Publication date Collection: 2020
                Volume: 13
                Pages: 497-511
                Affiliations
                [1 ]Department of Otorhinolaryngology, The First Affiliated Hospital of Chongqing Medical University , Chongqing 400016, People’s Republic of China
                Author notes
                Correspondence: GuoHua Hu Department of Otorhinolaryngology, The First Affiliated Hospital of Chongqing Medical University , Chongqing400016, People’s Republic of ChinaTel +86 23 89012945Fax +86 21 64085875 Email hghcq@sina.com
                Article
                Publisher ID: 237410
                DOI: 10.2147/OTT.S237410
                PMC ID: 6970617
                PubMed ID: 32021293
                SO-VID: 9b9903fb-608b-4b9a-9e29-3cf5f44887e3
                Copyright © © 2020 Wang et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 06 November 2019
                Date accepted : 01 January 2020
                Page count
                Figures: 7, Tables: 3, References: 38, Pages: 15
                Categories
                Subject: Original Research

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: hypopharyngeal carcinoma,epithelial-mesenchymal transition,akt/gsk-3β/snail,radioresistance,snail
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: hypopharyngeal carcinoma, epithelial-mesenchymal transition, akt/gsk-3β/snail, radioresistance, snail

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