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      Production of CCL20 from lung cancer cells induces the cell migration and proliferation through PI3K pathway

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          Abstract

          Tumour inflammatory microenvironment is considered to play a role in the sensitivity of tumour cells to therapies and prognosis of patients with lung cancer. The expression of CCL20, one of the critical chemoattractants responsible for inflammation cells recruitment, has been shown overexpressed in variety of tumours. This study aimed at investigating potential mechanisms of CCL20 function and production in human non‐small cell lung cancer ( NSCLC). Expression of CCL20 gene and protein in lung tissues of patients with NSCLC and NSCLC cells (A549) were determined. The interleukin ( IL)‐1β‐induced signal pathways in A549 and the effect of CCL20‐induced A549 cell migration and proliferation were determined using migration assays and cell‐alive monitoring system. Mechanisms of signal pathways involved in the migration of CCL20 were also studied. We initially found that NSCLC tumour tissues markedly overexpressed CCL20 in comparison with normal lung samples. In addition, IL‐1β could directly promote CCL20 production in lung cancer cells, which was inhibited by extracellular signal‐regulated kinase (ERK)1/2 inhibitor, p38 mitogen‐activated protein kinase (p38 MARP) inhibitor or PI3K inhibitors. CCL20 promoted lung cancer cells migration and proliferation in an autocrine manner via activation of ERK1/2‐ MAPK and PI3K pathways. Our data indicated that IL‐1β could stimulate CCL20 production from lung cancer cells through the activation of MAPKs and PI3K signal pathways, and the auto‐secretion of CCL20 could promote lung cancer cell migration and proliferation through the activation of ERK and PI3K signal pathways. Our results may provide a novel evidence that CCL20 could be a new therapeutic target for lung cancer.

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          The IL-1 family: regulators of immunity.

          Over recent years it has become increasingly clear that innate immune responses can shape the adaptive immune response. Among the most potent molecules of the innate immune system are the interleukin-1 (IL-1) family members. These evolutionarily ancient cytokines are made by and act on innate immune cells to influence their survival and function. In addition, they act directly on lymphocytes to reinforce certain adaptive immune responses. This Review provides an overview of both the long-established and more recently characterized members of the IL-1 family. In addition to their effects on immune cells, their involvement in human disease and disease models is discussed.
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            Selective Recruitment of Regulatory T Cell through CCR6-CCL20 in Hepatocellular Carcinoma Fosters Tumor Progression and Predicts Poor Prognosis

            Background Regulatory T cells (Tregs) are highly prevalent in tumor tissue and can suppress effective anti-tumor immune responses. However, the source of the increased tumor-infiltrating Tregs and their contribution to cancer progression remain poorly understood. Methodology/Principal Finding We here investigated the frequency, phenotype and trafficking property of Tregs and their prognostic value in patients with hepatocellular carcinoma (HCC). Our results showed that FoxP3+ Tregs highly aggregated and were in an activated phenotype (CD69+HLA-DRhigh) in the tumor site, where they can suppress the proliferation and INF-γ secretion of CD4+CD25− T cells. These tumor-infiltrating Tregs could be selectively recruited though CCR6-CCL20 axis as illustrated by (a) high expression of CCR6 on circulating Tregs and their selective migration to CCR6 ligand CCL20, and (b) correlation of distribution and expression between tumor-infiltrating Tregs and intratumoral CCL20. In addition, we found that the number of tumor-infiltrating Tregs was associated with cirrhosis background (P = 0.011) and tumor differentiation (P = 0.003), and was an independent prognostic factor for overall survival (HR = 2.408, P = 0.013) and disease-free survival (HR = 2.204, P = 0.041). The increased tumor-infiltrating Tregs predicted poorer prognosis in HCC patients. Conclusions The CCL20-CCR6 axis mediates the migration of circulating Tregs into tumor microenvironment, which in turn results in tumor progression and poor prognosis in HCC patients. Thus, blocking CCL20-CCR6 axis-mediated Treg migration may be a novel therapeutic target for HCC.
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              Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage.

              The efficacy of immune response to control human cancer remains controversial. It is particularly debated whether and to what extent the capacity of tumor-infiltrating dendritic cells (DC) to drive immunization can be turned off by transformed cells, leading to tumor-specific tolerance rather than immunization. To address this issue, we have characterized the DC isolated from human non-small cell lung cancer (NSCLC). These biopsy specimens contained CD11c(high) myeloid DC (mDC), but also CD11c(-) plasmacytoid DC (pDC) and a third DC subset expressing intermediate level of CD11c. Compared with peripheral blood, CD11c(high) tumor-infiltrating DC (TIDC) displayed a "semi-mature" phenotype, and TLR4 or TLR8 stimulation drove them to mature partially and to secrete limited amounts of cytokines. In contrast, most tumor-infiltrating pDC were immature but underwent partial maturation after TLR7 activation, whereas TLR9 ligation triggered low secretion of IFN-alpha. CD11c(int) mDC represented approximately 25% of total DC in tumoral and peritumoral tissues and expressed low levels of costimulatory molecules contrasting with high levels of the immunoinhibitory molecule B7-H1. Finally, the poor APC function of total TIDC even after TLR stimulation and the migratory response of both tumor-infiltrating mDC and pDC toward CCL21 and SDF-1 in vitro suggested their ability to compromise the tumor-specific immune response in draining lymph nodes in vivo. Further studies will be required to establish the specific role of the three TIDC subsets in tumor immunity and to draw conclusions for the design of therapeutic strategies.
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                Author and article information

                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                10 March 2016
                May 2016
                : 20
                : 5 ( doiID: 10.1111/jcmm.2016.20.issue-5 )
                : 920-929
                Affiliations
                [ 1 ] Department of Lung Medicine The First Affiliated HospitalWenzhou Medical University WenzhouChina
                [ 2 ] Zhongshan Hospital Biomedical Research Center Shanghai Institute of Clinical Bioinformatics Fudan University Center for Clinical BioinformaticsFudan University Shanghai Medical College ShanghaiChina
                Author notes
                [*] [* ] Correspondence to: Xiangdong WANG

                E‐mail: xiangdong.wang@ 123456clintransmed.org

                Chengshui CHEN

                E‐mail: chenchengshui@ 123456gmail.com

                [†]

                These authors contributed equally to this work.

                Article
                JCMM12781
                10.1111/jcmm.12781
                4831357
                26968871
                a816ec8f-de44-455b-ab86-d424965b280c
                © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 September 2015
                : 07 December 2015
                Page count
                Pages: 10
                Funding
                Funded by: Zhongshan Distinguished Professor Grant
                Funded by: National Nature Science Foundation of China
                Award ID: 91230204
                Award ID: 81270099
                Award ID: 81320108001
                Award ID: 81270131
                Award ID: 81300010
                Award ID: 81570075
                Funded by: Shanghai Committee of Science and Technology
                Award ID: 12JC1402200
                Award ID: 12431900207
                Award ID: 11410708600
                Award ID: 14431905100
                Funded by: Zhejiang Provincial Natural Science Foundation
                Award ID: Z2080988
                Award ID: Z15H010002
                Funded by: Zhejiang Provincial Science Technology Department Foundation
                Award ID: 2010C14011
                Funded by: Ministry of Education, Academic Special Science and Research Foundation for PhD Education
                Award ID: 20130071110043
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                jcmm12781
                May 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.8.6 mode:remove_FC converted:09.04.2016

                Molecular medicine
                lung,ccl20,cancer,pi3k,production,epithelium
                Molecular medicine
                lung, ccl20, cancer, pi3k, production, epithelium

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