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      The role of the AMOP domain in MUC4/Y-promoted tumour angiogenesis and metastasis in pancreatic cancer

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          Abstract

          Background

          MUC4 is a high molecular weight membrane protein that is overexpressed in pancreatic cancer (PC) and is associated with the development and progression of this disease. However, the exact mechanisms through which MUC4 domains promote these biological processes have rarely been studied, partly because of its high molecular weight, difficulty to overexpress it. Here, we use MUC4/Y, one of the MUC4 transcript variants, as a model molecule to investigate the AMOP-domain of MUC4(MUC/Y).

          Methods

          We used cell proliferation, migration, invasion and tube formation assays in vitro to explore the abilities of AMOP domain in PC. In vivo, the matrigel plug assay, orthotopic implantation and Kaplan-Meier survival curves were used to check the results we observed in vitro. Finally, we discovered the underlying mechanism through western blot and immunofluorescence.

          Results

          We found that MUC4/Y overexpression could enhance the angiogenic and metastatic properties of PC cells, both in vitro and in vivo. However, the deletion of AMOP domain could cutback these phenomena. Additionally, Kaplan-Meier survival curves showed that mice injected with MUC4/Y overexpressed cells had shorter survival time, compared with empty-vector-transfected cells (MUC4/Y-EV), or cells expressing MUC4/Y without the AMOP domain (MUC4/Y-AMOP ). Our data also showed that overexpression of MUC4/Y could activate NOTCH3 signaling, increasing the expression of downstream genes: VEGF-A, MMP-9 and ANG-2.

          Conclusions

          The AMOP domain had an important role in MUC4/Y (MUC4)-mediated tumour angiogenesis and metastasis of PC cells; and the NOTCH3 signaling was involved. These findings provided new insights into PC therapies. Our study also supplies a new method to study other high molecular membrane proteins.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13046-016-0369-0) contains supplementary material, which is available to authorized users.

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          Most cited references 60

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                Author and article information

                Contributors
                +86-25-83718836 , +86-25-82781992 , xuzekuan@njmu.edu.cn
                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
                10 June 2016
                10 June 2016
                2016
                : 35
                Affiliations
                [ ]Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu China
                [ ]Department of Pediatric Surgery, Nanjing Children’s Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu China
                [ ]Department of General Surgery, the People’s Hospital of Bozhou, Bozhou, Anhui China
                [ ]Department of General Surgery, Huai’an People’s Hospital, Xuzhou Medical College, Huai’an, Jiangsu China
                [ ]Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu China
                369
                10.1186/s13046-016-0369-0
                4902942
                27287498
                © The Author(s). 2016

                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.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81272712,30901421
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Oncology & Radiotherapy

                pancreatic cancer, notch3, metastasis, tumour angiogenesis, muc4/y-amop domain

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