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      STAT3 Pathway in Gastric Cancer: Signaling, Therapeutic Targeting and Future Prospects

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          Abstract

          Molecular signaling pathways play a significant role in the regulation of biological mechanisms, and their abnormal expression can provide the conditions for cancer development. The signal transducer and activator of transcription 3 (STAT3) is a key member of the STAT proteins and its oncogene role in cancer has been shown. STAT3 is able to promote the proliferation and invasion of cancer cells and induces chemoresistance. Different downstream targets of STAT3 have been identified in cancer and it has also been shown that microRNA (miR), long non-coding RNA (lncRNA) and other molecular pathways are able to function as upstream mediators of STAT3 in cancer. In the present review, we focus on the role and regulation of STAT3 in gastric cancer (GC). miRs and lncRNAs are considered as potential upstream mediators of STAT3 and they are able to affect STAT3 expression in exerting their oncogene or onco-suppressor role in GC cells. Anti-tumor compounds suppress the STAT3 signaling pathway to restrict the proliferation and malignant behavior of GC cells. Other molecular pathways, such as sirtuin, stathmin and so on, can act as upstream mediators of STAT3 in GC. Notably, the components of the tumor microenvironment that are capable of targeting STAT3 in GC, such as fibroblasts and macrophages, are discussed in this review. Finally, we demonstrate that STAT3 can target oncogene factors to enhance the proliferation and metastasis of GC cells.

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          Microenvironmental regulation of metastasis.

          Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves rate-limiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.
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            The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges

            Epithelial-to-Mesenchymal Transition (EMT) has been shown to be crucial in tumorigenesis where the EMT program enhances metastasis, chemoresistance and tumor stemness. Due to its emerging role as a pivotal driver of tumorigenesis, targeting EMT is of great therapeutic interest in counteracting metastasis and chemoresistance in cancer patients. The hallmark of EMT is the upregulation of N-cadherin followed by the downregulation of E-cadherin, and this process is regulated by a complex network of signaling pathways and transcription factors. In this review, we summarized the recent understanding of the roles of E- and N-cadherins in cancer invasion and metastasis as well as the crosstalk with other signaling pathways involved in EMT. We also highlighted a few natural compounds with potential anti-EMT property and outlined the future directions in the development of novel intervention in human cancer treatments. We have reviewed 287 published papers related to this topic and identified some of the challenges faced in translating the discovery work from bench to bedside.
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              LncRNA BCRT1 promotes breast cancer progression by targeting miR-1303/PTBP3 axis

              Background Long noncoding RNAs (lncRNAs) play crucial roles in tumor progression and are aberrantly expressed in various cancers. However, the functional roles of lncRNAs in breast cancer remain largely unknown. Methods Based on public databases and integrating bioinformatics analyses, the overexpression of lncRNA BCRT1 in breast cancer tissues was detected and further validated in a cohort of breast cancer tissues. The effects of lncRNA BCRT1 on proliferation, migration, invasion and macrophage polarization were determined by in vitro and in vivo experiments. Luciferase reporter assay and RNA immunoprecipitation (RIP) were carried out to reveal the interaction between lncRNA BCRT1, miR-1303, and PTBP3. Chromatin immunoprecipitation (ChIP) and RT-PCR were used to evaluate the regulatory effect of hypoxia-inducible factor-1α (HIF-1α) on lncRNA BCRT1. Results LncRNA BCRT1 was significantly upregulated in breast cancer tissues, which was correlated with poor prognosis in breast cancer patients. LncRNA BCRT1 knockdown remarkably suppressed tumor growth and metastasis in vitro and in vivo. Mechanistically, lncRNA BCRT1 could competitively bind with miR-1303 to prevent the degradation of its target gene PTBP3, which acts as a tumor-promoter in breast cancer. LncRNA BCRT1 overexpression could promote M2 polarization of macrophages, mediated by exosomes, which further accelerated breast cancer progression. Furthermore, lncRNA BCRT1 was upregulated in response to hypoxia, which was attributed to the binding of HIF-1α to HREs in the lncRNA BCRT1 promoter. Conclusions Collectively, these results reveal a novel HIF-1α/lncRNA BCRT1/miR-1303/PTBP3 pathway for breast cancer progression and suggest that lncRNA BCRT1 might be a potential biomarker and therapeutic target for breast cancer.
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                Author and article information

                Journal
                Biology (Basel)
                Biology (Basel)
                biology
                Biology
                MDPI
                2079-7737
                12 June 2020
                June 2020
                : 9
                : 6
                : 126
                Affiliations
                [1 ]Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz 5166616471, Iran; dvm.milad73@ 123456yahoo.com
                [2 ]Sabanci University Nanotechnology Research and Application Center (SUNUM), 34956 Tuzla, Istanbul, Turkey; alizarrabi@ 123456sabanciuniv.edu
                [3 ]Center of Excellence for Functional Surfaces and Interfaces (EFSUN), Faculty of Engineering and Natural Sciences, Sabanci University, 34956 Tuzla, Istanbul, Turkey
                [4 ]Department of Genetic Science, Tehran Medical Science Branch, Islamic Azad University, Tehran 1916893813, Iran; Sima.orouei@ 123456gmail.com
                [5 ]Laboratory for Stem Cell Research, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran; zarrin.vahideh2075@ 123456gmail.com
                [6 ]Department of Anatomical sciences, School of Medicine, Student Research Committee, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran; Ebrahimrahmani1374@ 123456gmail.com
                [7 ]Young Researchers and Elite Club, Tehran Medical Sciences, Islamic Azad University, Tehran 1916893813, Iran; Fzr2000_0007@ 123456yahoo.com
                [8 ]General Practitioner, Kerman University of Medical Sciences, Kerman 7616913555, Iran; Shima.mohamadi92@ 123456yahoo.com
                [9 ]Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran 1417414418, Iran; houshmandi.kia7@ 123456ut.ac.ir
                [10 ]Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz 5166616471, Iran; yasharqarehaghaj@ 123456gmail.com
                [11 ]Institute for Polymers, Composites and Biomaterials (IPCB), National Research Council (CNR), 80125 Naples, Italy; pooyanmakvandi@ 123456gmail.com
                [12 ]Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran
                [13 ]Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7616911319, Iran
                Author notes
                Author information
                https://orcid.org/0000-0001-6605-822X
                https://orcid.org/0000-0003-0391-1769
                https://orcid.org/0000-0003-3610-3311
                https://orcid.org/0000-0003-0280-4910
                https://orcid.org/0000-0003-2456-0961
                https://orcid.org/0000-0002-6341-9007
                Article
                biology-09-00126
                10.3390/biology9060126
                7345582
                32545648
                5304c08b-5509-4bb4-b28d-9d103a124237
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 16 May 2020
                : 04 June 2020
                Categories
                Review

                signal transducer and activator of transcription 3 (stat3),gastric cancer,microrna,long non-coding rna,cancer therapy,tumor microenvironment

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