Overexpression of High-Mobility Motor Box 1 in the Blood and Tissues of Patients with Head and Neck Squamous Cell Carcinoma

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Abstract

Introduction:

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world. Extra- and intra-cellular high-mobility motor box 1 (HMGB1) proteins are invovled in the pathogenesis and prognosis of cancer. Regarding this, the present study was conducted with the aim of investigating the expression of HMGB1 protein and mRNA levels in the blood, tumor tissue, and marginal normal tissue of patients with head and neck squamous cell carcinoma (HNSCC) using the quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC).

Materials and Methods:

This study was performed on 88 patients with HNSCC, who referred to the otorhinolaryngology and oral pathology departments, affiliated to Mashhad University of Medical Sciences, Mashhad, Iran, and a group of healthy subjects (i.e., control group) matched in terms of age and gender. RNA was collected from fresh tumor tissues, marginal tissues, and blood, followed by the implementation of quantitative PCR on the specimens. Furthermore, the expression of HMGB1 in tumor and normal margins was evaluated by means of IHC. The data were analyzed in SPSS software.

Results:

According to the results the expression levels of HMGB1 protein and mRNA were significantly higher in the tumor tissue than in the normal margin tissues (P<0.01). In addition, there was a significant correlation between histologic grading and the expression of HMGB1 protein and mRNA in tissues (P<0.05). Furthermore, the receiver operating characteristic curve of the HMGB1 mRNA in tissue was located closer to the theoretical 100% sensitivity.

Conclusion:

The findings revealed a higher increase in the levels of mRNA and HMGB1 protein in HNSCC, compared to those in the normal margin tissues. In addition, HMGB1 mRNA showed a significant expression in the tissue and blood of the patients with lymph node involvement.

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Most cited references 29

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HMG-1 as a late mediator of endotoxin lethality in mice.

H Wang, O Bloom, M Zhang … (1999)

Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.

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Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases.

A Taguchi, D C Blood, G del Toro … (2000)

The receptor for advanced glycation end products (RAGE), a multi-ligand member of the immunoglobulin superfamily of cell surface molecules, interacts with distinct molecules implicated in homeostasis, development and inflammation, and certain diseases such as diabetes and Alzheimer's disease. Engagement of RAGE by a ligand triggers activation of key cell signalling pathways, such as p21ras, MAP kinases, NF-kappaB and cdc42/rac, thereby reprogramming cellular properties. RAGE is a central cell surface receptor for amphoterin, a polypeptide linked to outgrowth of cultured cortical neurons derived from developing brain. Indeed, the co-localization of RAGE and amphoterin at the leading edge of advancing neurites indicated their potential contribution to cellular migration, and in pathologies such as tumour invasion. Here we demonstrate that blockade of RAGE-amphoterin decreased growth and metastases of both implanted tumours and tumours developing spontaneously in susceptible mice. Inhibition of the RAGE-amphoterin interaction suppressed activation of p44/p42, p38 and SAP/JNK MAP kinases; molecular effector mechanisms importantly linked to tumour proliferation, invasion and expression of matrix metalloproteinases.

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Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma.

Tobias Bald, Thomas Quast, Jennifer Landsberg … (2014)

Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma. The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established, but how the microenvironmental effects of UV radiation influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression, independent of its tumour-initiating effects. UV irradiation enhanced the expansion of tumour cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box 1 (HMGB1) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces. Our results not only reveal how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also show that the resulting inflammatory response catalyses reciprocal melanoma-endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism in human melanomas by histopathologists. Angiotropism represents a hitherto underappreciated mechanism of metastasis that also increases the likelihood of intravasation and haematogenous dissemination. Consistent with our findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and their association with endothelial cells represent rational strategies to specifically interfere with metastatic progression.

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Author and article information

Journal

Journal ID (nlm-ta): Iran J Otorhinolaryngol

Journal ID (iso-abbrev): Iran J Otorhinolaryngol

Journal ID (publisher-id): IJO

Title: Iranian Journal of Otorhinolaryngology

Publisher: Mashhad University of Medical Sciences (Mashhad, Iran )

ISSN (Print): 2251-7251

ISSN (Electronic): 2251-726X

Publication date (Print): September 2018

Volume: 30

Issue: 100

Pages: 261-271

Affiliations

[1 ] Dental Research Center, Mashhad University of Medical Sciences, Mashhad, Iran .

[2 ] Cancer Molecular Pathology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

[3 ] Department of Otorhinolaryngology, Mashhad University of Medical Sciences, Mashhad, Iran.

[4 ] Department of Biostatic, Mashhad University of Medical Sciences, Mashhad, Iran.

Author notes

[* ]CORRESPONDING AUTHORS: ORAL AND MAXILLOFACIAL DISEASE RESEARCH CENTER, MASHHAD UNIVERSITY OF MEDICAL SCIENCES, MASHHAD, IRAN. E-MEALI: MOHTASHAMN@MUMS.AC.IR

Article

Publisher ID: ijo-30-261

PMC ID: 6147264

PubMed ID: 30245980

SO-VID: c7b7c7fa-0efc-41bb-baec-1360d552bb68

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, ( http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Overexpression of High-Mobility Motor Box 1 in the Blood and Tissues of Patients with Head and Neck Squamous Cell Carcinoma

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Abstract

Introduction:

Materials and Methods:

Results:

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Related collections

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Most cited references 29

HMG-1 as a late mediator of endotoxin lethality in mice.

Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases.

Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma.

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