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      Epiregulin reprograms cancer-associated fibroblasts and facilitates oral squamous cell carcinoma invasion via JAK2-STAT3 pathway

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          Abstract

          Background

          Local resident normal fibroblasts (NFs) are the major source of cancer-associated fibroblasts (CAFs), which are distinguishable from NFs by their tumor-supportive properties. However, the mechanism and the effects underlying the transition of NFs to CAFs in oral squamous cell carcinoma (OSCC) remain unclear.

          Methods

          Five pairs of matching primary NFs and CAFs derived from OSCC patients were sent for RNA sequencing. Epiregulin (EREG) expression was analyzed by IHC in fibroblasts from OSCC patients. The role of EREG in the NF-CAF transition and the consequential effects on OSCC progression were examined by upregulation/downregulation of EREG in NFs/CAFs both in vitro and in vivo.

          Results

          Here, we identified epiregulin (EREG) as the most remarkably upregulated gene in CAFs. High EREG expression in CAFs correlated with higher T stage, deeper invasion and inferior worst pattern of invasion (WPOI) in OSCC patients and predicted shorter overall survival. Overexpression of EREG in NFs activated the CAF phenotype. Mechanistically, the JAK2/STAT3 pathway was enhanced by EREG in parallel with increased IL-6 expression, which could be inhibited by the JAK2 inhibitor AG490. Recombinant IL-6 upregulated the JAK2/STAT3/EREG pathway in a feedback loop. Moreover, EREG-induced CAF activation promoted the epithelial-mesenchymal transition (EMT) necessary for migration and invasion, which was dependent on JAK2/STAT3 signaling and IL-6. In vivo, EREG expression in stroma fibroblasts promoted tumor growth with high stromal α-SMA, phospho-JAK2/STAT3, and IL-6 expression and upregulated EMT in HSC3 cells.

          Conclusions

          EREG is essential for the NF-CAF transformation needed to induce EMT of tumor cells in a JAK2-STAT3- and IL-6-dependent manner in OSCC.

          Electronic supplementary material

          The online version of this article (10.1186/s13046-019-1277-x) contains supplementary material, which is available to authorized users.

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          Most cited references27

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          Targeting the interleukin-6/Jak/stat pathway in human malignancies.

          The Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway was discovered 20 years ago as a mediator of cytokine signaling. Since this time, more than 2,500 articles have been published demonstrating the importance of this pathway in virtually all malignancies. Although there are dozens of cytokines and cytokine receptors, four Jaks, and seven Stats, it seems that interleukin-6-mediated activation of Stat3 is a principal pathway implicated in promoting tumorigenesis. This transcription factor regulates the expression of numerous critical mediators of tumor formation and metastatic progression. This review will examine the relative importance and function of this pathway in nonmalignant conditions as well as malignancies (including tumor intrinsic and extrinsic), the influence of other Stats, the development of inhibitors to this pathway, and the potential role of inhibitors in controlling or eradicating cancers.
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            MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer.

            Cancer-associated fibroblasts (CAF) are a major constituent of the tumor stroma, but little is known about how cancer cells transform normal fibroblasts into CAFs. microRNAs (miRNA) are small noncoding RNA molecules that negatively regulate gene expression at a posttranscriptional level. Although it is clearly established that miRNAs are deregulated in human cancers, it is not known whether miRNA expression in resident fibroblasts is affected by their interaction with cancer cells. We found that in ovarian CAFs, miR-31 and miR-214 were downregulated, whereas miR-155 was upregulated when compared with normal or tumor-adjacent fibroblasts. Mimicking this deregulation by transfecting miRNAs and miRNA inhibitors induced a functional conversion of normal fibroblasts into CAFs, and the reverse experiment resulted in the reversion of CAFs into normal fibroblasts. The miRNA-reprogrammed normal fibroblasts and patient-derived CAFs shared a large number of upregulated genes highly enriched in chemokines, which are known to be important for CAF function. The most highly upregulated chemokine, CCL5, (C-C motif ligand 5) was found to be a direct target of miR-214. These results indicate that ovarian cancer cells reprogram fibroblasts to become CAFs through the action of miRNAs. Targeting these miRNAs in stromal cells could have therapeutic benefit. The mechanism by which quiescent fibroblasts are converted into CAFs is unclear. The present study identifies a set of 3 miRNAs that reprogram normal fibroblasts to CAFs. These miRNAs may represent novel therapeutic targets in the tumor microenvironment. ©2012 AACR.
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              Fibroblasts as architects of cancer pathogenesis.

              Studies of epithelial cancers (i.e., carcinomas) traditionally focused on transformation of the epithelium (i.e., the cancer cells) and how aberrant signaling within the cancer cells modulates the surrounding tissue of origin. In more recent decades, the normal cells, blood vessels, molecules, and extracellular components that surround the tumor cells, collectively known as the "tumor microenvironment" or "stroma", have received increasing attention and are now thought to be key regulators of tumor initiation and progression. Of particular relevance to the work reviewed herein are the fibroblasts, which make up the major cell type within the microenvironment of most carcinomas. Due to their inherent heterogeneity, plasticity, and function, it is perhaps not surprising that fibroblasts are ideal modulators of normal and cancerous epithelium; however, these aspects also present challenges if we are to interrupt their tumor-supportive functions. Here, we review the current body of knowledge and the many questions that still remain about the special entity known as the cancer-associated fibroblast. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. Copyright © 2012. Published by Elsevier B.V.
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                Author and article information

                Contributors
                yoghurtmed@163.com
                jingyueshadow@126.com
                879269339@qq.com
                sissi.117@hotmail.com
                songyuxian1986@126.com
                jakjone@163.com
                572004532@qq.com
                hxf681008@sina.com
                puyumei1981@126.com
                wangzhiyong67@163.com
                +86-2583620140 , niyanhong12@163.com
                +86-2583620101 , qghunjkq@163.com
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                24 June 2019
                24 June 2019
                2019
                : 38
                : 274
                Affiliations
                [1 ]ISNI 0000 0001 2314 964X, GRID grid.41156.37, Department of Oral & Maxillofacial Surgery Nanjing Stomatological Hospital, , Medical School of Nanjing University, ; 30 Zhongyang Road, Nanjing, 210008 China
                [2 ]ISNI 0000 0001 2314 964X, GRID grid.41156.37, Central Laboratory Nanjing Stomatological Hospital, , Medical School of Nanjing University, ; 30 Zhongyang Road, Nanjing, 210008 China
                [3 ]ISNI 0000 0001 2314 964X, GRID grid.41156.37, Department of Oral Pathology Nanjing Stomatological Hospital, , Medical School of Nanjing University, ; Nanjing, China
                [4 ]ISNI 0000 0001 2360 039X, GRID grid.12981.33, Department of Oral & Maxillofacial Surgery Sun Yat-Sen Memorial Hospital, , Sun Yat-Sen University, ; Guangzhou, China
                Article
                1277
                10.1186/s13046-019-1277-x
                6591968
                31234944
                3dc0ecf7-dd30-4912-8cb1-9068658c05ad
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 11 December 2018
                : 12 June 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81772880
                Award ID: 81702680
                Funded by: Nanjing Medical Science and Technique Development Foundation
                Award ID: YKK16164
                Award ID: QRX17083
                Funded by: Jiangsu Provincial Key Medical Discipline
                Award ID: since 2017
                Award Recipient :
                Funded by: Nanjing Municipal Key Medical Laboratory Constructional Project Funding
                Award ID: since 2016
                Award Recipient :
                Funded by: Center of Nanjing Clinical Medicine of tumor project
                Award ID: since 2014
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                oral squamous cell carcinoma,cancer-associated fibroblasts,epiregulin,transition,metastasis,invasion

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