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Mucin 17 Inhibits the Progression of Human Gastric Cancer by Limiting Inflammatory Responses Through a MYH9-P53-Rhoa Regulatory

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Mucin 17 Inhibits the Progression of Human Gastric Cancer by Limiting Inflammatory Responses Through a MYH9-P53-Rhoa Regulatory Yang et al. Journal of Experimental & Clinical Cancer Research (2019) 38:283 https://doi.org/10.1186/s13046-019-1279-8 RESEARCH Open Access Mucin 17 inhibits the progression of human gastric cancer by limiting inflammatory responses through a MYH9- p53-RhoA regulatory feedback loop Bing Yang1†, Aiwen Wu1†, Yingqi Hu1, Cuijian Tao1, Ji Ming Wang2, Youyong Lu1 and Rui Xing1* Abstract Background: Mucins are key components of the mucosal barrier in the stomach that protects epithelia from carcinogenic effects of chronic inflammation. Analysis of The Cancer Genome Atlas database indicated that mucin- 17 (MUC17) was more highly expressed in gastric cancer (GC) specimens, with favourable prognosis for patients. To explore the underlying mechanisms, we investigated the potential role of MUC17 in controlling chronic gastric inflammation. Methods: We initially quantified the expression of MUC17 and inflammatory factor, as well as the association of MUC17 with survive in GC using immunohistochemistry. To establish how the inflammatory factors affect MUC17 expression, we explored luciferase reporter, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift (EMSA) assays. The role and mechanism that MUC17 plays in inflammation-induced cell proliferation was examined in AGS cells with reduced MUC17 expression and MKN45 cells overexpressing a truncated MUC17. Results: We found MUC17 was induced by inflammatory cytokines in GC cells via CDX1upregulation. MUC17 thus inactivated NFκB to inhibit GC cell proliferation in response to pro-inflammatory cytokines. We also revealed that the function of MUC17 was dependent on its conserved epidermal growth factor domain and on downstream sequences to enable its interaction with myosin-9, resulting in a sustained regulatory feedback loop between myosin-9, p53, and RhoA, and then activation of p38 to negatively regulate the NFκB pathway in GC cells. This mechanism was also confirmed in vivo. Conclusions: Our study demonstrates MUC17 as a GC suppressor protein which has the therapeutic potential for human GC. Keywords: Inflammation, Gastric cancer, MUC17, Survive Backgound barrier often leads to chronic inflammation, a major Gastric cancer (GC) is one of the most common and ag- contributor to the development of GC [2]. One of the gressive cancer types throughout the world [1]. Most main components of the mucosal barrier that protects GC associates with dysfunction of the mucosal barrier in the underlying stomach epithelium is the mucin family the stomach, the first line of defence against pathogens of high molecular-weight glycosylated proteins [3, 4], and inflammation. Impairment of the gastric mucosal with 21 mucin genes identified (MUC1-MUC21) so far. In recent years, mucins have also been found to be both * Correspondence: [email protected] therapeutic targets and biomarkers predicting the prog- †Bing Yang and Aiwen Wu contributed equally to this work. nosis of various cancers [5]. Studies suggest that mucins 1 Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and may act as tumour-suppressing genes. For example, Translational Research (Ministry of Education), Peking University Cancer −/− Hospital & Institute, Fu-Cheng Road 52#, Hai-Dian District, Beijing 100142, MUC2 mice develop colon adenomas, suggesting that China MUC2 is involved in the suppression of colorectal Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This 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. Yang et al. Journal of Experimental & Clinical Cancer Research (2019) 38:283 Page 2 of 13 cancer [6]. Further, their expression is regulated by in- in a small preliminary experiment using PASS (NCSS, flammatory stimulants. For example, IL1β and IL17A East Kaysville, UT, USA). A pathologist blinded to the both promote MUC5B expression in target cells [7]. IL8 purpose of the study read the microarray in this study and (CXCL8) has also been shown to regulate MUC5AC ex- gave an unbiased report. Our study was conducted in ac- pression [8], while IL4 and IL13 both increase MUC2 cordance with the Helsinki Declaration, and was approved mRNA expression [9]. However, the biological role of by the Institutional Ethical Standards Committee with in- mucins in GC development, and association with inflam- formed consent from patients. mation is not well understood. To establish the link between mucins and inflammation RNA isolation and polymerase chain reaction (PCR) in GC progression, we analysed transcriptional data re- Total cellular RNA was isolated from cells using TRIzol trieved from The Cancer Genome Atlas (TCGA) and dis- Reagent (Invitrogen) and reverse transcribed using the covered that MUC17 was consistently expressed at high cDNA reverse transcription kit (Invitrogen). The expres- levels in GC tissues, which is associated with favourable sion levels of MUC17 and CDX1 mRNA were analysed patient survival after surgery. We therefore investigated using SYBR Green qPCR reagent (Transgen Ltd., Beijing, the expression of MUC17 in a patient cohort to more pre- China) using an ABI7500 qPCR System (Applied Biosys- cisely establish a link between MUC17 and inflammation tems, Foster City, CA, USA). The primer sequences are in the development of GC. Here, we report that MUC17 listed in Additional file 3: Table S1. The relative expression inhibits inflammatory response in the stomach to protect levels of each gene were normalized against an actin en- ΔΔ the epithelial cell from carcinogenesis. dogenous control using the 2- Ct method. Materials and methods Luciferase assay Clinical samples Luciferase reporter assays were performed using a Dual- Experiments were conducted in accordance with the Luciferase Reporter Assay System (Promega, Madison, Helsinki Declaration 2013 and were approved by the In- WI, USA) with the pGL3 basic luciferase reporter system. stitutional Ethical Standards Committee of Beijing Can- The promoter sequence was chosen by using UCSC data- cer Hospital. Written informed consent was obtained base based on the peaks of H3K4Me3 and H3K27AC. The from all patients. All GC samples were collected from promoter regions were cloned into pGL3-basic plasmid the Beijing Cancer Hospital and were evaluated by a using SmaI and XhoI (Endonucleases were purchased centralized pathological review group. from NEB, MA, USA; T4 DNA ligase was purchased from Promega). Promoter-specific luciferase constructs (the Cell lines and transfection primers used for construction of the plasmid are listed in AGS cells were purchased from the American Type Cul- Additional file 3: Table S1) and empty pGL3-basic were ture Collection (ATCC, Manassas, VA, USA), MKN45 co-transfected with a control Renilla luciferase construct cells were purchased from the Cobioer (Nanjing, China). into cells using Lipofectamine 2000 (Invitrogen). The lu- Mycoplasma testing was negative. AGS and MKN45 ciferase signal was first normalized to the Renilla lucifer- cells were cultured in Dulbecco’s modified Eagle’s ase signal and then normalized to the signal from the medium (Gibco, Grand Island, NY, USA) with 10% or empty pGL3 plasmid. All experiments were performed in- 20% fetal bovine serum (Gibco). Cells were maintained dependently at least three times. at 37 °C under 5% CO2. The transfection was performed by using Lipofecta- Electrophoretic mobility shift assay (EMSA) mine 2000 (Invitrogen, Carlsbad, CA, USA) following Nuclear extracts were first isolated from AGS cells and the manufacturer’s instructions. then nuclear proteins (3 μg) were mixed with biotin- labeled probes (Additional file 3: Table S1) containing the Immunohistochemistry MUC17 consensus sequence (50fmol). These were then GC specimen without chemotherapy and radiotherapy be- incubated at 25 °C for 20 min. The protein-DNA mixtures fore surgery were random collected. Immunohistochemis- were separated from unbound probe using a 6% polyacryl- try was performed using a Dako Real Envision Detection amide gel at 4 °C for 2 h in a Tris-glycine-EDTA running System (Dako, Glostrup, Denmark). Slides were incubated buffer. The gel was then transferred and detected using an with a primary antibody specific to MUC17 (Sigma-Al- enhanced chemiluminescence (ECL) detection system drich, St. Louis, MO, USA), followed by incubation with a (Sage Creation, Beijing, China). biotinylated secondary antibody and enzyme conjugate (Dako). These then stained with 3,3′-diaminobenzidine Chromatin immunoprecipitation (ChIP) assay and counterstained with hematoxylin. The sample size ChIP assays were performed using an Agarose CHIP Kit was determined using the positive MUC17 staining rates (ThermoFishier, Carlsbad, CA, USA) and the manufacturer’s Yang et al. Journal of Experimental & Clinical Cancer Research (2019) 38:283 Page 3 of 13 protocols. The primary antibodies used were specific to min, following the protocols of a cell cycle detection kit CDX1 (Abcam, Cambridge, MA, USA) and Histone H4 (Beyotime Ltd., Jiangsu Province, China). The cells were
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