Identification of ESM1 overexpressed in head and neck squamous cell carcinoma

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Abstract

Background

Endocan, also known as endothelial cell specific molecule-1 (ESM1), is a 50 kDa soluble proteoglycan which is frequently overexpressed in many cancer types. Whether it is dysregulated in head and neck squamous cell carcinoma (HNSCC) has not been investigated.

Methods

We analyzed the expression of ESM1 using bioinformatics analysis based on data from The Cancer Genome Atlas (TCGA), and then validated that ESM1 was significantly overexpressed in human HNSCC at the protein level using immunohistochemistry. We also analyzed the genes co-expressed with ESM1 in HNSCC.

Results

The most correlated gene was angiopoietin-2 (ANGPT2), a molecule which regulates physiological and pathological angiogenesis. Several transcription factor binding motifs including SMAD3, SMAD4, SOX3, SOX4, HIF2A and AP-1 components were significantly enriched in the promoter regions of the genes co-expressed with ESM1. Further analysis based on ChIP-seq data from the ENCODE (Encyclopedia of DNA Elements) project revealed that AP-1 is an important regulator of ESM1 expression.

Conclusions

Our results revealed a dysregulation of ESM1 and a potential regulatory mechanism for the co-expression network in HNSCC.

Electronic supplementary material

The online version of this article (10.1186/s12935-019-0833-y) contains supplementary material, which is available to authorized users.

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Most cited references 37

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Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.

M. L. Gillison, W Koch, R B Capone … (2000)

High-risk human papillomaviruses (HPVs) are etiologic agents for anogenital tract cancers and have been detected in head and neck squamous cell carcinomas (HNSCCs). We investigated, retrospectively, an etiologic role for HPVs in a large series of patients with HNSCC. Tumor tissues from 253 patients with newly diagnosed or recurrent HNSCC were tested for the presence of HPV genome by use of polymerase chain reaction (PCR)-based assays, Southern blot hybridization, and in situ hybridization. The viral E6 coding region was sequenced to confirm the presence of tumor-specific viral isolates. Exons 5-9 of the TP53 gene were sequenced from 166 specimens. The hazard of death from HNSCC in patients with and without HPV-positive tumors was determined by proportional hazards regression analysis. HPV was detected in 62 (25%) of 253 cases (95% confidence interval [CI] = 19%-30%). High-risk, tumorigenic type HPV16 was identified in 90% of the HPV-positive tumors. HPV16 was localized specifically by in situ hybridization within the nuclei of cancer cells in preinvasive, invasive, and lymph node disease. Southern blot hybridization patterns were consistent with viral integration. Poor tumor grade (odds ratio [OR] = 2.4; 95% CI = 1.2- 4.9) and oropharyngeal site (OR = 6.2; 95% CI = 3.1-12.1) independently increased the probability of HPV presence. As compared with HPV-negative oropharyngeal cancers, HPV-positive oropharyngeal cancers were less likely to occur among moderate to heavy drinkers (OR = 0.17; 95% CI = 0.05-0.61) and smokers (OR = 0.16; 95% CI = 0.02-1.4), had a characteristic basaloid morphology (OR = 18.7; 95% CI = 2.1-167), were less likely to have TP53 mutations (OR = 0.06; 95% CI = 0.01-0. 36), and had improved disease-specific survival (hazard ratio [HR] = 0.26; 95% CI = 0.07-0.98). After adjustment for the presence of lymph node disease (HR = 2.3; 95% CI = 1.4- 3.8), heavy alcohol consumption (HR = 2.6; 95% CI = 1.4-4.7), and age greater than 60 years old (HR = 1.4; 95% CI = 0.8-2.3), all patients with HPV-positive tumors had a 59% reduction in risk of death from cancer when compared with HPV-negative HNSCC patients (HR = 0.41; 95% CI = 0.20-0.88). These data extend recent molecular and epidemiologic studies and strongly suggest that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis.

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Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.

Ulrike Fiedler, Yvonne Reiss, Marion Scharpfenecker … (2006)

The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the receptor tyrosine kinase Tie-2 (refs. 1,2). Paracrine Ang-1-mediated activation of Tie-2 acts as a regulator of vessel maturation and vascular quiescence. In turn, the antagonistic ligand Ang-2 acts by an autocrine mechanism and is stored in endothelial Weibel-Palade bodies from where it can be rapidly released upon stimulation. The rapid release of Ang-2 implies functions of the angiopoietin-Tie system beyond its established role during vascular morphogenesis as a regulator of rapid vascular responses. Here we show that mice deficient in Ang-2 (encoded by the gene Angpt2) cannot elicit an inflammatory response in thioglycollate-induced or Staphylococcus aureus-induced peritonitis, or in the dorsal skinfold chamber model. Recombinant Ang-2 restores the inflammation defect in Angpt2(-/-) mice. Intravital microscopy showed normal TNF-alpha-induced leukocyte rolling in the vasculature of Angpt2(-/-)mice, but rolling cells did not firmly adhere to activated endothelium. Cellular experiments showed that Ang-2 promotes adhesion by sensitizing endothelial cells toward TNF-alpha and modulating TNF-alpha-induced expression of endothelial cell adhesion molecules. Together, these findings identify Ang-2 as an autocrine regulator of endothelial cell inflammatory responses. Ang-2 thereby acts as a switch of vascular responsiveness exerting a permissive role for the activities of proinflammatory cytokines.

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Angiopoietins in angiogenesis.

Ernesta Fagiani, Gerhard Christofori (2013)

Tie-1 and Tie-2 tyrosine kinase receptors are expressed specifically on vascular endothelial cells and on a certain subtype of macrophages implicated in angiogenesis, thus, they have been a major focus of angiogenesis research. Tie-1 and Tie-2 are essential for vascular maturation during developmental, physiological and pathological angiogenesis. Angiopoietin 1-4 (Ang-1-4) have been identified as bona fide ligands of the Tie-2 receptor, while Tie-1 remains an orphan receptor which is able to heterodimerize with Tie-2 and to modulate Tie-2 signal transduction. The most exhaustively studied angiopoietins are Ang-1 and Ang-2. Ang-1 is a critical player in vessel maturation and it mediates migration, adhesion and survival of endothelial cells. Ang-2 disrupts the connections between the endothelium and perivascular cells and promotes cell death and vascular regression. Yet, in conjunction with VEGF, Ang-2 promotes neo-vascularization. Hence, angiopoietins exert crucial roles in the angiogenic switch during tumor progression, and increased expression of Ang-2 relative to Ang-1 in tumors correlates with poor prognosis. Its central role in the regulation of physiological and pathological angiogenesis makes the angiopoietin/Tie signaling pathway a therapeutically attractive target for the treatment of vascular disease and cancer. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

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Author and article information

Contributors

Hongbo Xu:

ORCID: http://orcid.org/0000-0001-9946-2915

xuhongbo76@163.com

Xiaohong Chen: trchxh@163.com

Zhigang Huang: huangzhigang1968@sohu.com

Journal

Journal ID (nlm-ta): Cancer Cell Int

Journal ID (iso-abbrev): Cancer Cell Int

Title: Cancer Cell International

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2867

Publication date (Electronic): 2 May 2019

Publication date PMC-release: 2 May 2019

Publication date Collection: 2019

Volume: 19

Electronic Location Identifier: 118

Affiliations

ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Department of Otolaryngology-Head and Neck Surgery, Key Laboratory of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, , Capital Medical University, ; Beijing, 100730 China

Author information

Hongbo Xu http://orcid.org/0000-0001-9946-2915

Article

Publisher ID: 833

DOI: 10.1186/s12935-019-0833-y

PMC ID: 6498655

PubMed ID: 31073279

SO-VID: 05822dfa-e6c2-4491-8b87-91b468198103

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 : 3 July 2018

Date accepted : 20 April 2019

Funding

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

Award ID: 81670946

Award Recipient : Hongbo Xu

Funded by: FundRef http://dx.doi.org/10.13039/501100009331, Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support;

Award ID: XMLX201507

Award Recipient : Hongbo Xu

Funded by: Beijing Tongren Hospital, Capital Medical University scientific research backbone fund

Award ID: 2015-YJJ-GGL-002

Award Recipient : Hongbo Xu

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: esm1,head and neck cancer,regulation

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: esm1, head and neck cancer, regulation

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Identification of ESM1 overexpressed in head and neck squamous cell carcinoma

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Cancer Immunotherapy

Most cited references 37

Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.

Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation.

Angiopoietins in angiogenesis.

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Cited by 13

Most referenced authors 1,248