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      JAK/STAT pathway: Extracellular signals, diseases, immunity, and therapeutic regimens

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          Abstract

          Janus kinase/signal transduction and transcription activation (JAK/STAT) pathways were originally thought to be intracellular signaling pathways that mediate cytokine signals in mammals. Existing studies show that the JAK/STAT pathway regulates the downstream signaling of numerous membrane proteins such as such as G-protein-associated receptors, integrins and so on. Mounting evidence shows that the JAK/STAT pathways play an important role in human disease pathology and pharmacological mechanism. The JAK/STAT pathways are related to aspects of all aspects of the immune system function, such as fighting infection, maintaining immune tolerance, strengthening barrier function, and cancer prevention, which are all important factors involved in immune response. In addition, the JAK/STAT pathways play an important role in extracellular mechanistic signaling and might be an important mediator of mechanistic signals that influence disease progression, immune environment. Therefore, it is important to understand the mechanism of the JAK/STAT pathways, which provides ideas for us to design more drugs targeting diseases based on the JAK/STAT pathway. In this review, we discuss the role of the JAK/STAT pathway in mechanistic signaling, disease progression, immune environment, and therapeutic targets.

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          Most cited references272

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          New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer

          Epithelial-mesenchymal transition (EMT) is a cellular programme that is known to be crucial for embryogenesis, wound healing and malignant progression. During EMT, cell-cell and cell-extracellular matrix interactions are remodelled, which leads to the detachment of epithelial cells from each other and the underlying basement membrane, and a new transcriptional programme is activated to promote the mesenchymal fate. In the context of neoplasias, EMT confers on cancer cells increased tumour-initiating and metastatic potential and a greater resistance to elimination by several therapeutic regimens. In this Review, we discuss recent findings on the mechanisms and roles of EMT in normal and neoplastic tissues, and the cell-intrinsic signals that sustain expression of this programme. We also highlight how EMT gives rise to a variety of intermediate cell states between the epithelial and the mesenchymal state, which could function as cancer stem cells. In addition, we describe the contributions of the tumour microenvironment in inducing EMT and the effects of EMT on the immunobiology of carcinomas.
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            Myeloid-derived suppressor cells as regulators of the immune system.

            Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.
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              Targeting the IL-6/JAK/STAT3 signalling axis in cancer

              The IL-6/JAK/STAT3 pathway is aberrantly hyperactivated in many types of cancer, and such hyperactivation is generally associated with a poor clinical prognosis. In the tumour microenvironment, IL-6/JAK/STAT3 signalling acts to drive the proliferation, survival, invasiveness, and metastasis of tumour cells, while strongly suppressing the antitumour immune response. Thus, treatments that target the IL-6/JAK/STAT3 pathway in patients with cancer are poised to provide therapeutic benefit by directly inhibiting tumour cell growth and by stimulating antitumour immunity. Agents targeting IL-6, the IL-6 receptor, or JAKs have already received FDA approval for the treatment of inflammatory conditions or myeloproliferative neoplasms and for the management of certain adverse effects of chimeric antigen receptor T cells, and are being further evaluated in patients with haematopoietic malignancies and in those with solid tumours. Novel inhibitors of the IL-6/JAK/STAT3 pathway, including STAT3-selective inhibitors, are currently in development. Herein, we review the role of IL-6/JAK/STAT3 signalling in the tumour microenvironment and the status of preclinical and clinical investigations of agents targeting this pathway. We also discuss the potential of combining IL-6/JAK/STAT3 inhibitors with currently approved therapeutic agents directed against immune-checkpoint inhibitors.
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                Author and article information

                Contributors
                Journal
                Front Bioeng Biotechnol
                Front Bioeng Biotechnol
                Front. Bioeng. Biotechnol.
                Frontiers in Bioengineering and Biotechnology
                Frontiers Media S.A.
                2296-4185
                23 February 2023
                2023
                : 11
                : 1110765
                Affiliations
                [1] 1 Department of Pharmacy , School of Medicine , Sir Run Run Shaw Hospital , Zhejiang University , Hangzhou, China
                [2] 2 Oujiang Laboratory , Key Laboratory of Alzheimer’s Disease of Zhejiang Province , Institute of Aging , Wenzhou Medical University , Wenzhou, China
                [3] 3 Department of Clinical Pharmacology , Xiangya Hospital , Central South University , Changsha, China
                [4] 4 Hunan Key Laboratory of Pharmacogenetics , Institute of Clinical Pharmacology , Central South University , Changsha, China
                [5] 5 Department of Orthopaedic Surgery , The Third Affiliated Hospital , Guangzhou Medical University , Guangzhou, China
                [6] 6 Department of Pharmacy , Wuhan First Hospital , Wuhan, China
                [7] 7 Department of Research , Center for Prevention and Therapy of Gynecological Cancers , Buddhist Tzu Chi General Hospital , Hualien, Taiwan
                [8] 8 Department of Thoracic Surgery , Xiangya Hospital , Central South University , Changsha, China
                Author notes

                Edited by: Hsien-Yeh Chen, National Taiwan University, Taiwan

                Reviewed by: CLifford Liongue, Deakin University, Australia

                Meghdad Abdollahpour-Alitappeh, Larestan University of Medical Sciences, Iran

                *Correspondence: Jie Mei, meijie7201@ 123456163.com ; Peng-Yuan Wang, py.wang@ 123456ojlab.ac.cn

                This article was submitted to Nanobiotechnology, a section of the journal Frontiers in Bioengineering and Biotechnology

                Article
                1110765
                10.3389/fbioe.2023.1110765
                9995824
                36911202
                d49c6349-1dba-42e3-a62a-1935a7997f7b
                Copyright © 2023 Hu, Bian, Rong, Wang, Song, Huang, Zeng, Mei and Wang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 November 2022
                : 13 February 2023
                Funding
                Funded by: Ministry of Science and Technology , doi 10.13039/100007225;
                Award ID: 2019YFE0113000
                Funded by: National Natural Science Foundation of China-Guangdong Joint Fund , doi 10.13039/501100014857;
                Award ID: 31870988
                PW thanks the support from the Ministry of Science and Technology of China (2019YFE0113000); the National Natural and Science Foundation of China (31870988).
                Categories
                Bioengineering and Biotechnology
                Review

                jak/stat,disease progression,immune environment,mechanotransduction,therapeutic targets

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