Global Proteomics-based Identification and Validation of Thymosin Beta-4 X-Linked as a Prognostic Marker for Head and Neck Squamous Cell Carcinoma

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Abstract

Head and neck squamous cell carcinoma (HNSCC) represents a major health concern worldwide. We applied the matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) to analyze paired normal (N) and tumor (T) samples from head and neck squamous cell carcinoma as well as liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis in HNSCC cell lines to identify tumor-associated biomarkers. Our results showed a number of proteins found to be over-expressed in HNSCC. We identified thymosin beta-4 X-linked (TMSB4X) is one of the most significant candidate biomarkers. Higher TMSB4X expression in the tumor was found by N/T-paired HNSCC samples at both RNA and protein level. Overexpression of TMSB4X was found significantly associated with poor prognosis of overall survival (OS, P = 0.006) and recurrence-free survival (RFS, P = 0.013) in HNSCC patients. Silencing of TMSB4X expression in HNSCC cell line reduced the proliferation and invasion ability in vitro, as well as inhibited the cervical lymph node metastasis in vivo. Altogether, our global proteomics analysis identified that TMSB4X is a newly discovered biomarker in HNSCC whose functions resulted in enhanced proliferation and metastasis in vitro and in vivo. TMSB4X may be a potential therapeutic target for treating HNSCC patients.

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A hospital-based case-control study of matched pairs was conducted to explore (a) the relationship between the use of betel quid chewing, cigarette smoking, alcohol drinking and oral cancer and (b) synergism between these factors. The case group consisted of 104 male and 3 female oral cancer patients and these were compared with 194 male and 6 female matched controls. We found by univariate analysis that alcohol consumption, smoking, betel quid chewing, educational level and occupation were associated with oral cancer. The adjusted odds ratios were to be found elevated in patients who were smoking and betel quid chewing. After adjusting for education and occupation covariates, the incidence of oral cancer was computed to be 123-fold higher in patients who smoked, drank alcohol and chewed betel quid than in abstainers. The synergistic effects of alcohol, tobacco smoke and betel quid in oral cancer were clearly demonstrated, but there was a statistically significant association between oral cancer and betel quid chewing alone. Swallowing betel quid juice (saliva extract of betel quid produced by chewing) or including unripened betel fruit in the quid both seemed to enhance the risks of contracting oral cancer.

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Gregory Hannigan, Shoukat Dedhar, A Troussard (2004)

Cancer development requires the acquisition of several capabilities that include increased replicative potential, anchorage and growth-factor independence, evasion of apoptosis, angiogenesis, invasion of surrounding tissues and metastasis. One protein that has emerged as promoting many of these phenotypes when dysregulated is integrin-linked kinase (ILK), a unique intracellular adaptor and kinase that links the cell-adhesion receptors, integrins and growth factors to the actin cytoskeleton and to a range of signalling pathways. The recent findings of increased levels of ILK in various cancers, and that inhibition of ILK expression and activity is antitumorigenic, makes ILK an attractive target for cancer therapeutics.

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Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men.

Ariana Znaor, Paul Brennan, Vendhan Gajalakshmi … (2003)

Oral, pharyngeal and esophageal cancers are 3 of the 5 most common cancer sites in Indian men. To assess the effect of different patterns of smoking, chewing and alcohol drinking in the development of the above 3 neoplasms and to determine the interaction among these habits, we conducted a case-control study in Chennai and Trivandrum, South India. The cases included 1,563 oral, 636 pharyngeal and 566 esophageal male cancer patients who were compared with 1,711 male disease controls from the 2 centers as well as 1,927 male healthy hospital visitors from Chennai. We observed a significant dose-response relationship for duration and amount of consumption of the 3 habits with the development of the 3 neoplasms. Tobacco chewing emerged as the strongest risk factor for oral cancer, with the highest odds ratio (OR) for chewing products containing tobacco of 5.05 [95% confidence internal (CI) 4.26-5.97]. The strongest risk factor for pharyngeal and esophageal cancers was tobacco smoking, with ORs of 4.00 (95% CI 3.07-5.22) and 2.83 (95% CI 2.18-3.66) in current smokers, respectively. An independent increase in risk was observed for each habit in the absence of the other 2. For example, the OR of oral cancers for alcohol drinking in never smokers and never chewers was 2.56 (95% CI 1.42-4.64) and that of esophageal cancers was 3.41 (95% CI 1.46-7.99). Furthermore, significant decreases in risks for all 3 cancer sites were observed in subjects who quit smoking even among those who had quit smoking 2-4 years before the interview. Copyright 2003 Wiley-Liss, Inc.

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Author and article information

Contributors

Tsung-Ching Lai: chuching@gate.sinica.edu.tw

Yu-Chuan (Jack) Li: jaak88@gmail.com

Michael Hsiao: mhsiao@gate.sinica.edu.tw

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 22 August 2017

Publication date PMC-release: 22 August 2017

Publication date Collection: 2017

Volume: 7

Electronic Location Identifier: 9031

Affiliations

[1 ]ISNI 0000 0001 2287 1366, GRID grid.28665.3f, The Ph.D. Program for Translational Medicine, , College of Medical Science and Technology, Taipei Medical University and Academia Sinica, ; Taipei, Taiwan

[2 ]ISNI 0000 0001 2287 1366, GRID grid.28665.3f, Genomics Research Center, , Academia Sinica, ; Taipei, Taiwan

[3 ]ISNI 0000 0004 0639 0994, GRID grid.412897.1, Division of Oral and Maxillofacial Surgery, , Department of Dentistry, Taipei Medical University Hospital, ; Taipei, Taiwan

[4 ]ISNI 0000 0004 0622 9252, GRID grid.417380.9, Department of Density, , Yuan’s General Hospital, ; Kaohsiung, Taiwan

[5 ]ISNI 0000 0004 0572 9992, GRID grid.415011.0, Departments of Density, , Kaohsiung Veterans General Hospital, ; Kaohsiung, Taiwan

[6 ]Department of Pathology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan

[7 ]ISNI 0000 0000 9337 0481, GRID grid.412896.0, Department of Pathology, , College of Medicine, Taipei Medical University, ; Taipei, Taiwan

[8 ]ISNI 0000 0000 9337 0481, GRID grid.412896.0, Graduate Institute of Biomedical Informatics, , College of Medicine Science and Technology, Taipei Medical University, ; Taipei, Taiwan

[9 ]ISNI 0000 0000 9476 5696, GRID grid.412019.f, Department of Biochemistry, , College of Medicine, Kaohsiung Medical University, ; Kaohsiung, Taiwan

Author information

Li-Hsing Chi http://orcid.org/0000-0002-4476-2600

Wei-Min Chang http://orcid.org/0000-0002-6899-4043

Article

Publisher ID: 9539

DOI: 10.1038/s41598-017-09539-w

PMC ID: 5567379

PubMed ID: 28831179

SO-VID: eacacd61-e278-43ce-bcfc-e70bb4e76eed

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 7 December 2016

Date accepted : 26 July 2017

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Global Proteomics-based Identification and Validation of Thymosin Beta-4 X-Linked as a Prognostic Marker for Head and Neck Squamous Cell Carcinoma

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Most cited references 39

Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan.

Integrin-linked kinase: a cancer therapeutic target unique among its ILK.

Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men.

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