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 54

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Vascular-specific growth factors and blood vessel formation.

G Yancopoulos, S. Davis, N W Gale … (2000)

A recent explosion in newly discovered vascular growth factors has coincided with exploitation of powerful new genetic approaches for studying vascular development. An emerging rule is that all of these factors must be used in perfect harmony to form functional vessels. These new findings also demand re-evaluation of therapeutic efforts aimed at regulating blood vessel growth in ischaemia, cancer and other pathological settings.

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XB130 promotes proliferation and invasion of gastric cancer cells

Min Shi, Dayong Zheng, Li Sun … (2014)

Background XB130 has been reported to be expressed by various types of cells such as thyroid cancer and esophageal cancer cells, and it promotes the proliferation and invasion of thyroid cancer cells. Our previous study demonstrated that XB130 is also expressed in gastric cancer (GC), and that its expression is associated with the prognosis, but the role of XB130 in GC has not been well characterized. Methods In this study, we investigated the influence of XB130 on gastric tumorigenesis and metastasis in vivo and in vitro using the MTT assay, clonogenic assay, BrdU incorporation assay, 3D culture, immunohistochemistry and immunofluorescence. Western blot analysis was also performed to identify the potential mechanisms involved. Results The proliferation, migration, and invasion of SGC7901 and MNK45 gastric adenocarcinoma cell lines were all significantly inhibited by knockdown of XB130 using small hairpin RNA. In a xenograft model, tumor growth was markedly inhibited after shXB130-transfected GC cells were implanted into nude mice. After XB130 knockdown, GC cells showed a more epithelial-like phenotype, suggesting an inhibition of the epithelial-mesenchymal transition (EMT) process. In addition, silencing of XB130 reduced the expression of p-Akt/Akt, upregulated expression of epithelial markers including E-cadherin, α-catenin and β-catenin, and downregulated mesenchymal markers including fibronectin and vimentin. Expression of oncoproteins related to tumor metastasis, such as MMP2, MMP9, and CD44, was also significantly reduced. Conclusions These findings indicate that XB130 enhances cell motility and invasiveness by modulating the EMT-like process, while silencing XB130 in GC suppresses tumorigenesis and metastasis, suggesting that it may be a potential therapeutic target.

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Endogenous angiogenin in endothelial cells is a general requirement for cell proliferation and angiogenesis.

Richard K. Olson, SHUMEI LIU, De-Fu Hu … (2005)

Angiogenin is an angiogenic protein that undergoes nuclear translocation in endothelial cells where it accumulates in the nucleolus and stimulates rRNA transcription, a rate-limiting step in ribosome biogenesis, protein translation, and cell growth. Here, we report that angiogenin is required for cell proliferation induced by various other angiogenic proteins including acidic and basic fibroblast growth factors (aFGF and bFGF), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF). Downregulation of angiogenin in endothelial cells by small interfering RNA (siRNA) and antisense results in a decrease in rRNA transcription, ribosome biogenesis, and cell proliferation induced by these angiogenic factors. Inhibitors of the nuclear translocation of angiogenin abolish the angiogenic activities of these factors. Stable angiogenin antisense transfection in HeLa cells reduces tumor angiogenesis in athymic mice despite the elevated expression level of bFGF and VEGF. Thus, nuclear angiogenin assumes an essential role in endothelial cell proliferation and is necessary for angiogenesis induced by other angiogenic factors. Angiogenin-stimulated rRNA transcription in endothelial cells may thus serve as a crossroad in the process of angiogenesis induced by various angiogenic factors.

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Author and article information

Contributors

Zekuan Xu: +86-25-83718836 , +86-25-82781992 , xuzekuan@njmu.edu.cn

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 10 June 2016

Publication date PMC-release: 10 June 2016

Publication date Collection: 2016

Volume: 35

Electronic Location Identifier: 91

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

Article

Publisher ID: 369

DOI: 10.1186/s13046-016-0369-0

PMC ID: 4902942

PubMed ID: 27287498

SO-VID: 4237603f-6fc5-400e-b3e9-17fc644e0bac

License:

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

Date received : 23 January 2016

Date accepted : 1 June 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81272712,30901421

Award Recipient : Zekuan Xu

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

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

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ScienceOpen disciplines: Oncology & Radiotherapy

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

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

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

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Karger: Oncology

Most cited references 54

Vascular-specific growth factors and blood vessel formation.

XB130 promotes proliferation and invasion of gastric cancer cells

Endogenous angiogenin in endothelial cells is a general requirement for cell proliferation and angiogenesis.

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