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Seitz HK. A narrative review on alcohol and alimentary tract cancer with special emphasis on acetaldehyde and oxidative stress. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2025. [PMID: 40378880 DOI: 10.1055/a-2588-6849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/19/2025]
Abstract
Approximately 4% of all cancer cases worldwide are caused by alcohol consumption (oropharynx, larynx, esophagus, stomach, colorectum, liver and the female breast). Various mechanisms contribute to ethanol-mediated carcinogenesis, including the action of acetaldehyde, the first metabolite of ethanol oxidation and oxidative stress primarily promoted through the induction of cytochrome P4502E1. Acetaldehyde is toxic and carcinogenic, binds to DNA and proteins, inhibits the oxidative defense- and the nuclear repair system, and prevents DNA methylation. High levels of acetaldehyde occur through increased production in the presence of a hyperactive alcohol dehydrogenase (ADH1C*1,1) or decreased degradation in the presence of low active aldehyde dehydrogenase (ALDH2*1,2). In addition, microbes of the upper alimentary tract and the colorectum effectively produce acetaldehyde from ethanol. In addition, ethanol induces cytochrome P4502E1 resulting in an enhanced ethanol metabolism and the generation of reactive oxygen species (ROS). ROS may cause lipid peroxidation (LPO) with the LPO-products 4-hydroxynonenal or malondialdehyde, which may form highly carcinogenic etheno DNA-adducts CYP2E1 is also involved in the activation of a variety of dietary and tobacco procarcinogens and in the degradation of retinoic acid. Alcohol also influences tumor promotion, such as epigenetics with a change in DNA methylation and histone modification, and affects a variety of cancer genes and signaling pathways. Preventive measures include reducing alcohol consumption, quitting smoking and keeping good oral hygiene. Alcohol consumers - especially when they smoke or belong to genetic risk groups - should be regularly checked for cancer of the upper alimentary tract, for alcohol- associated liver disease, and for breast cancer. Cessation or reduction of alcohol consumption definitively reduces cancer risk.
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Affiliation(s)
- Helmut Karl Seitz
- Centre of Liver- and Alcohol Diseases, ETHIANUM Klinik, Heidelberg, Germany
- Internal Medicine, Gastroenetrology, Alcohol Research, Faculty of Medicine, University of Heidelberg, Heidelberg, Germany
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Kumar M, Kumar A, Srivastav A, Ghosh A, Kumar D. Genomic and molecular landscape of gallbladder cancer elucidating pathogenic mechanisms novel therapeutic targets and clinical implications. Mutat Res 2024; 830:111896. [PMID: 39754821 DOI: 10.1016/j.mrfmmm.2024.111896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/19/2024] [Accepted: 12/19/2024] [Indexed: 01/06/2025]
Abstract
Gallbladder cancer (GBC) is an aggressive malignancy with a poor prognosis, often diagnosed at advanced stages due to subtle early symptoms. Recent studies have provided a comprehensive view of GBC's genetic and mutational landscape, uncovering crucial pathways involved in its pathogenesis. Environmental exposures, particularly to heavy metals, have been linked to elevated GBC risk. Established signaling pathways, including hormonal, apoptotic, metabolic, inflammatory, and DNA damage repair pathways, are integral to GBC progression, and evidence points to the involvement of specific germline and somatic mutations in its development. Key mutations in genes such as KRAS, TP53, IDH1/2, ERBB, PIK3CA, MET, MYC, BRAF, MGMT, CDKN2A and p16 have been identified as contributors to tumorigenesis, with additional alterations including chromosomal aberrations and epigenetic modifications. These molecular insights reveal several potential therapeutic targets that could address the limited treatment options for GBC. Promising therapeutic avenues under investigation include immune checkpoint inhibitors, tyrosine kinase inhibitors, tumor necrosis factor-related apoptosis-inducing ligands (TRAIL), and phytochemicals. Numerous clinical trials are assessing the efficacy of these targeted therapies. This review provides a detailed examination of GBC's genetic and mutational underpinnings, highlighting critical pathways and emerging therapeutic strategies. We discuss the implications of germline and somatic mutations for early detection and individualized treatment, aiming to bridge current knowledge gaps. By advancing our understanding of GBC's molecular profile, we hope to enhance diagnostic accuracy and improve treatment outcomes, ultimately paving the way for precision medicine approaches in managing GBC.
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Affiliation(s)
- Manishankar Kumar
- School of Health Sciences and Technology, UPES, Dehradun, Uttarakhand 248007, India
| | - Arun Kumar
- Mahavir Cancer Institute and Research Centre, Phulwarisharif, Patna, Bihar 801505, India
| | - Abhinav Srivastav
- Mahavir Cancer Institute and Research Centre, Phulwarisharif, Patna, Bihar 801505, India
| | - Ashok Ghosh
- Mahavir Cancer Institute and Research Centre, Phulwarisharif, Patna, Bihar 801505, India
| | - Dhruv Kumar
- School of Health Sciences and Technology, UPES, Dehradun, Uttarakhand 248007, India.
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Tannenbaum AP, Lozar T, Lu C, Schumacher M, Golfinos A, Dinh HQ, Taylor N, Kimple RJ, Yang D, Harari PM, Lambert PF, Lloyd RV, Hu R. Uncommon and Challenging Phenotypes of High-Risk Human Papillomavirus-Associated Head and Neck Carcinomas Revealed by High-Throughput Studies. Head Neck Pathol 2024; 18:112. [PMID: 39436498 PMCID: PMC11496466 DOI: 10.1007/s12105-024-01707-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 09/19/2024] [Indexed: 10/23/2024]
Abstract
BACKGROUND HPV- associated squamous cell carcinoma (SCC) is uncommon in non-oropharynx sites and not well characterized. This study aims to investigate uncommon phenotypes of HPV-associated head and neck carcinoma, the prevalence and morphologic spectrum of HPV-associated SCC in the oral cavity, larynx and hypopharynx. METHOD P16 immunostaining and HPV E6/7 in situ hybridization (ISH) were performed on tissue microarrays comprised of SCCs from different anatomic sites: oropharynx (n = 270), hypopharynx (n = 52), oral cavity (n = 95) and larynx (n = 123). Tumors were classified as HPV-associated based on a positive E6/7 ISH testing. RNA sequencing was performed on several selected cases. RESULT 66% oropharynx SCCs (OPSCCs) were HPV-associated; all were p16/HPV testing concordant except one which was p16 negative. The p16-/HPV + OPSCC resembled similar gene expression signature with p16+/HPV + OPSCCs by transcriptome analysis. 6/95 (6%) oral cavity SCCs were HPV-associated, all from male patients and 5/6 (83%) arose from the floor of mouth. Morphologically, 3/6 (50%) showed keratinizing SCC and 5/6 (83%) demonstrated HPV-associated squamous dysplasia in adjacent mucosa. 1/123 (less than 1%) larynx SCCs and 0/52 hypopharynx SCCs were HPV-associated. CONCLUSION Although uncommon, p16 negative HPV-associated OPSCC can occur, emphasizing the importance of judicious HPV testing. The morphology of HPV-associated oral cavity SCCs may deviate from prototypic nonkeratinizing SCC, making them difficult to recognize. Presence of HPV-associated squamous dysplasia could serve as a morphologic clue.
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Affiliation(s)
- Alex P Tannenbaum
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Taja Lozar
- McArdle Laboratory for Cancer Research, Madison, WI, 53705, USA
- University of Ljubljana, Ljubljana, Slovenia
| | - Changxue Lu
- Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Megan Schumacher
- Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Athena Golfinos
- McArdle Laboratory for Cancer Research, Madison, WI, 53705, USA
| | - Huy Q Dinh
- McArdle Laboratory for Cancer Research, Madison, WI, 53705, USA
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Natalie Taylor
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA
- Dane County Medical Examiner's Office, McFarland, WI, 53558, USA
| | - Randall J Kimple
- McArdle Laboratory for Cancer Research, Madison, WI, 53705, USA
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - David Yang
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Paul M Harari
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Paul F Lambert
- McArdle Laboratory for Cancer Research, Madison, WI, 53705, USA
- Department of Human Oncology, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Ricardo V Lloyd
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Rong Hu
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, 53705, USA.
- McArdle Laboratory for Cancer Research, Madison, WI, 53705, USA.
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Hurník P, Režnarová J, Chyra Z, Motyka O, Putnová BM, Čermáková Z, Blažek T, Fománek M, Gaykalova D, Buchtová M, Ševčíková T, Štembírek J. Enhancing oral squamous cell carcinoma prediction: the prognostic power of the worst pattern of invasion and the limited impact of molecular resection margins. Front Oncol 2023; 13:1287650. [PMID: 38188288 PMCID: PMC10766711 DOI: 10.3389/fonc.2023.1287650] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 11/28/2023] [Indexed: 01/09/2024] Open
Abstract
Objective Oral squamous cell carcinoma (OSCC) originates from the mucosal lining of the oral cavity. Almost half of newly diagnosed cases are classified as advanced stage IV disease, which makes resection difficult. In this study, we investigated the pathological features and mutation profiles of tumor margins in OSCC. Methods We performed hierarchical clustering of principal components to identify distinct patterns of tumor growth and their association with patient prognosis. We also used next-generation sequencing to analyze somatic mutations in tumor and marginal tissue samples. Results Our analyses uncovered that the grade of worst pattern of invasion (WPOI) is strongly associated with depth of invasion and patient survival in multivariable analysis. Mutations were primarily detected in the DNA isolated from tumors, but several mutations were also identified in marginal tissue. In total, we uncovered 29 mutated genes, mainly tumor suppressor genes involved in DNA repair including BRCA genes; however none of these mutations significantly correlated with a higher chance of relapse in our medium-size cohort. Some resection margins that appeared histologically normal harbored tumorigenic mutations in TP53 and CDKN2A genes. Conclusion Even histologically normal margins may contain molecular alterations that are not detectable by conventional histopathological methods, but NCCN classification system still outperforms other methods in the prediction of the probability of disease relapse.
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Affiliation(s)
- Pavel Hurník
- Institute of Clinical and Molecular Pathology, University Hospital Ostrava, Ostrava, Czechia
- Institute of Clinical and Molecular Pathology, Faculty of Medicine, University of Ostrava, Ostrava, Czechia
- Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Jana Režnarová
- Department of Oral and Maxillofacial Surgery, University Hospital Ostrava, Ostrava, Czechia
- Department of Craniofacial Surgery, Faculty of Medicine, Ostrava University, Ostrava, Ostrava, Czechia
| | - Zuzana Chyra
- Department of Hematooncology, University Hospital Ostrava, Ostrava, Czechia
| | - Oldřich Motyka
- Department of Environmental Engineering, VSB-Technical University of Ostrava, Ostrava, Czechia
| | - Barbora Moldovan Putnová
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czechia
- Department of Pathological Morphology and Parasitology, University of Veterinary Sciences Brno, Brno, Czechia
| | - Zuzana Čermáková
- Department of Oncology, University Hospital Ostrava, Ostrava, Czechia
| | - Tomáš Blažek
- Department of Oncology, University Hospital Ostrava, Ostrava, Czechia
| | - Martin Fománek
- Department of Otorhinolaryngology, University Hospital Ostrava, Ostrava, Czechia
| | - Daria Gaykalova
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States
- Department of Otorhinolaryngology-Head and Neck Surgery, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore, MD, United States
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States
| | - Marcela Buchtová
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czechia
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia
| | - Tereza Ševčíková
- Department of Hematooncology, University Hospital Ostrava, Ostrava, Czechia
| | - Jan Štembírek
- Department of Oral and Maxillofacial Surgery, University Hospital Ostrava, Ostrava, Czechia
- Department of Craniofacial Surgery, Faculty of Medicine, Ostrava University, Ostrava, Ostrava, Czechia
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czechia
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Lam RCT, Hui CWC, Wong CH, Lo KW, Tsang ACM, Hui EP, Chan ATC, Ma BBY. Preclinical evaluation of the VEGF/Ang2 bispecific nanobody BI 836880 in nasopharyngeal carcinoma models. Invest New Drugs 2023; 41:699-709. [PMID: 37572231 DOI: 10.1007/s10637-023-01384-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 07/11/2023] [Indexed: 08/14/2023]
Abstract
Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is endemic to parts of Asia and overexpression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α are common in NPC. Anti-vascular agents have known clinical activity in patients with recurrent/ metastatic NPC and in this study, we investigated the anti-tumor effect of BI 836880, a humanized bispecific nanobody against VEGF and angiopoietin-2 (Ang2), in preclinical models of EBV-positive and EBV-negative NPC. The efficacy of BI 836880 was also compared with bevacizumab, a recombinant humanized monoclonal antibody against VEGF. We found that BI 836880 could exert growth-inhibitory effect on endothelial cells (HUVEC-C) and the EBV-negative NPC cell line (HK1), but to a lesser extent in the EBV-positive NPC cell lines, C17C and C666-1. In patients-derived xenograft (PDX) models of NPC - Xeno-2117 and Xeno-666, BI 836880 could suppress tumor growth and Ki67, as well as induce tumor necrosis and reduce microvessel density. Moreover, treatment with BI 836880 increased the level of macrophage infiltration in both PDX tumor models of NPC, suggesting that BI 836880 may exert immunomodulatory effect on the NPC immune microenvironment. When compared with bevacizumab, BI 836880 appeared to show at least comparable activity as bevacizumab in terms of its anti-proliferative and anti-angiogenic effects. This study showed that BI 836880 has anti-proliferative, anti-angiogenic and possibly immunomodulatory effect in clinical models of NPC, therefore the dual targeting of VEGF and Ang2 signaling in NPC should be further investigated.
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Affiliation(s)
- Rachel C T Lam
- Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong , SAR, China
| | - Connie W C Hui
- State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, SAR, China
- Cancer Drug Testing Unit, Li Ka Shing Institute of Health Sciences, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - C H Wong
- State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, SAR, China
- Cancer Drug Testing Unit, Li Ka Shing Institute of Health Sciences, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - K W Lo
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Anna C M Tsang
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Edwin P Hui
- State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, SAR, China
| | - Anthony T C Chan
- State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, SAR, China
- Cancer Drug Testing Unit, Li Ka Shing Institute of Health Sciences, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Brigette B Y Ma
- State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, SAR, China.
- Cancer Drug Testing Unit, Li Ka Shing Institute of Health Sciences, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong, SAR, China.
- Department of Clinical Oncology, Prince of Wales Hospital, Shatin, NT, Hong Kong SAR, China.
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Williams A, Gutgesell L, de Wet L, Selman P, Dey A, Avineni M, Kapoor I, Mendez M, Brown R, Lamperis S, Blajszczak C, Bueter E, Kregel S, Vander Griend DJ, Szmulewitz R. SOX 2 expression in prostate cancer drives resistance to nuclear hormone receptor signaling inhibition through the WEE1/CDK1 signaling axis. Cancer Lett 2023; 565:216209. [PMID: 37169162 DOI: 10.1016/j.canlet.2023.216209] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 04/28/2023] [Accepted: 05/01/2023] [Indexed: 05/13/2023]
Abstract
The development of androgen receptor signaling inhibitor (ARSI) drug resistance in prostate cancer (PC) remains therapeutically challenging. Our group has described the role of sex determining region Y-box 2 (SOX2) overexpression in ARSI-resistant PC. Continuing this work, we report that NR3C1, the gene encoding glucocorticoid receptor (GR), is a novel SOX2 target in PC, positively regulating its expression. Similar to ARSI treatment, SOX2-positive PC cells are insensitive to GR signaling inhibition using a GR modulating therapy. To understand SOX2-mediated nuclear hormone receptor signaling inhibitor (NHRSI) insensitivity, we performed RNA-seq in SOX2-positive and -negative PC cells following NHRSI treatment. RNA-seq prioritized differentially regulated genes mediating the cell cycle, including G2 checkpoint WEE1 Kinase (WEE1) and cyclin-dependent kinase 1 (CDK1). Additionally, WEE1 and CDK1 were differentially expressed in PC patient tumors dichotomized by high vs low SOX2 gene expression. Importantly, pharmacological targeting of WEE1 (WEE1i) in combination with an ARSI or GR modulator re-sensitizes SOX2-positive PC cells to nuclear hormone receptor signaling inhibition in vitro, and WEE1i combined with ARSI significantly slowed tumor growth in vivo. Collectively, our data suggest SOX2 predicts NHRSI resistance, and simultaneously indicates the addition of WEE1i to improve therapeutic efficacy of NHRSIs in SOX2-positive PC.
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Affiliation(s)
- Anthony Williams
- Department of Medicine, Section of Hematology & Oncology, The University of Chicago Medical Center, 5841 S Maryland Avenue, Chicago, IL, 60637, USA
| | - Lisa Gutgesell
- Department of Pathology, University of Illinois at Chicago, 909 S Wolcott Avenue, Chicago, IL, 60612, USA
| | - Larischa de Wet
- Department of Pathology, University of Illinois at Chicago, 909 S Wolcott Avenue, Chicago, IL, 60612, USA
| | - Phillip Selman
- Department of Medicine, Section of Hematology & Oncology, The University of Chicago Medical Center, 5841 S Maryland Avenue, Chicago, IL, 60637, USA
| | - Arunangsu Dey
- Department of Medicine, Section of Hematology & Oncology, The University of Chicago Medical Center, 5841 S Maryland Avenue, Chicago, IL, 60637, USA
| | - Mahati Avineni
- Department of Medicine, Section of Hematology & Oncology, The University of Chicago Medical Center, 5841 S Maryland Avenue, Chicago, IL, 60637, USA
| | - Isha Kapoor
- Department of Medicine, Section of Hematology & Oncology, The University of Chicago Medical Center, 5841 S Maryland Avenue, Chicago, IL, 60637, USA
| | - Megan Mendez
- Department of Medicine, Section of Hematology & Oncology, The University of Chicago Medical Center, 5841 S Maryland Avenue, Chicago, IL, 60637, USA
| | - Ryan Brown
- Department of Pathology, University of Illinois at Chicago, 909 S Wolcott Avenue, Chicago, IL, 60612, USA
| | - Sophia Lamperis
- Department of Medicine, Section of Hematology and Oncology, Northwestern University - Feinberg School of Medicine, 420 E Superior St, Chicago, IL, 60611, USA
| | - Chuck Blajszczak
- Department of Medicine, Section of Hematology & Oncology, The University of Chicago Medical Center, 5841 S Maryland Avenue, Chicago, IL, 60637, USA
| | - Eric Bueter
- Department of Medicine, Section of Hematology & Oncology, The University of Chicago Medical Center, 5841 S Maryland Avenue, Chicago, IL, 60637, USA; Committee on Cancer Biology, The University of Chicago Medical Center, 5841 S Maryland Avenue, Chicago, IL, 60637, USA
| | - Steve Kregel
- Department of Cancer Biology, Loyola University - Cardinal Bernardin Cancer Center, 2160 S 1st Ave, Maywood, IL, 60153, USA
| | - Donald J Vander Griend
- Department of Pathology, University of Illinois at Chicago, 909 S Wolcott Avenue, Chicago, IL, 60612, USA
| | - Russell Szmulewitz
- Department of Medicine, Section of Hematology & Oncology, The University of Chicago Medical Center, 5841 S Maryland Avenue, Chicago, IL, 60637, USA.
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Bharti A, Qayoom S, Jaiswal R, Agarwal P, Singh RK, Agarwal SP, Bhalla S, Makker A, Goel MM. Can dual staining with p16 and Ki67 be biomarkers of epithelial dysplasia in oral lesions? J Cancer Res Ther 2022; 18:1003-1008. [PMID: 36149153 DOI: 10.4103/jcrt.jcrt_40_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
BACKGROUND Oral carcinogenesis is a multistage process with epithelial dysplasia as a premalignant condition. There is a significant inter-observer variation in diagnosing and grading the oral epithelial dysplasia. As human papillomavirus (HPV) is believed to have à strong relationship with oral carcinogenesis, using P16 as a biomarker may help in identifying the cells which may be undergoing the malignant transformation. However, due to the low specificity of P16, dual staining test P16INK4/Ki67 might be a better promising marker for identifying the transformed cells. This study was designed to evaluate the dual expression of P16 and Ki67 as a promising biomarker for dysplasia and their correlation with clinicopathological factors. MATERIALS AND METHODS Immunohistochemical analysis for p16 and ki67 was performed on 30 premalignant oral lesions and 36 oral squamous cell carcinoma (OSCC) by dual staining using the CINtec PLUS kit. RESULTS CINtec positivity was observed only in leukoplakia with dysplasia (46.7%) and squamous cell carcinoma (25%). None of the cases of leukoplakia without dysplasia or oral submucosal fibrosis stained positive for CINtec plus staining. In leukoplakia with dysplasia, there was no significant association with any of the clinicopathological parameters studied. In OSCC cases, alcohol intake showed statistically significant association with CINtec positivity. CONCLUSION P16INK4/Ki67 assessment by dual staining is a promising biomarker for identifying dysplasia in cases with diagnostic dilemmas.
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Affiliation(s)
- Anju Bharti
- Department of Pathology, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India
| | - Sumaira Qayoom
- Department of Pathology, KGMU, Lucknow, Uttar Pradesh, India
| | - Riddhi Jaiswal
- Department of Pathology, KGMU, Lucknow, Uttar Pradesh, India
| | - Preeti Agarwal
- Department of Pathology, KGMU, Lucknow, Uttar Pradesh, India
| | - R K Singh
- Department of Maxillofacial Surgery & Otorhinolaryngology, KGMU, Lucknow, Uttar Pradesh, India
| | - S P Agarwal
- Department of Maxillofacial Surgery & Otorhinolaryngology, KGMU, Lucknow, Uttar Pradesh, India
| | - Shalini Bhalla
- Department of Pathology, KGMU, Lucknow, Uttar Pradesh, India
| | - Annu Makker
- Department of Biochemistry, Prasad Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Madhu Mati Goel
- Department of Pathology, KGMU, Lucknow, Uttar Pradesh, India
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A Case of HPV-Associated Oropharyngeal Squamous Cell Carcinoma with Block-Like, Partial Loss of p16 Expression. Head Neck Pathol 2022; 16:1251-1256. [PMID: 35771403 PMCID: PMC9729667 DOI: 10.1007/s12105-022-01463-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Accepted: 05/22/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Oropharyngeal squamous cell carcinoma is frequently associated with high-risk HPV infection, which confers a good prognosis. Immunohistochemistry for p16 is used as a surrogate for HPV status, but discrepant results are occasionally seen. Here, we report a case with a unique pattern of partial loss of p16. METHODS A 63 year old male presented with a base of tongue nonkeratinizing squamous cell carcinoma and a large metastatic neck mass. The primary lesion and multiple regions of the metastatic mass were assessed with p16 immunohistochemistry, RNA in situ hybridization for high-risk HPV, and HPV16 genome sequencing. RESULTS The primary lesion was p16 negative, and the metastatic neck mass had large, confluent regions that were either strongly p16 positive or entirely p16 negative. All of these regions were positive for high-risk HPV with identical HPV16 genomes. CONCLUSION This unusual case illustrates a potential diagnostic pitfall, and it raises important questions regarding molecular mechanisms and prognostic implications of p16 staining in oropharyngeal squamous cell carcinoma.
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Cruciani S, Garroni G, Pala R, Barcessat ARP, Facchin F, Ventura C, Fozza C, Maioli M. Melatonin finely tunes proliferation and senescence in hematopoietic stem cells. Eur J Cell Biol 2022; 101:151251. [PMID: 35772322 DOI: 10.1016/j.ejcb.2022.151251] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 06/17/2022] [Accepted: 06/20/2022] [Indexed: 11/19/2022] Open
Abstract
Human hematopoietic stem/progenitor cells (HSPCs) are pluripotent cells that gradually lose their self-renewal and regenerative potential, to give rise to mature cells of the hematopoietic system by differentiation. HSPC infusion is used to restore hematopoietic function in patients with a variety of onco-hematologic and immune-mediated disorders. The functionality of these cells is therefore of great importance to ensure the homeostasis of the hematopoietic system. Melatonin plays an important role as immunomodulatory and oncostatic hormone. In the present manuscript, we aimed at evaluating the activity of melatonin in modulating HSPC senescence, in the attempt to improve their hemopoietic regenerative potential. We exposed HSPCs to melatonin, in different conditions, and then analyzed the expression of genes regulating cell cycle and cell senescence. Moreover, we assessed cell senescence by β-galactosidase and telomerase activity. Our results showed the ability of melatonin to counteract HSPC senescence, thus paving the way for enhanced efficiency in their clinical application.
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Affiliation(s)
- Sara Cruciani
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; Consorzio Interuniversitario "Istituto Nazionale Biostrutture e Biosistemi" (INBB), Viale delle Medaglie d'Oro 305, 00136, Roma (RM).
| | - Giuseppe Garroni
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy.
| | - Renzo Pala
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy.
| | - Ana Rita Pinheiro Barcessat
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; Health and Biological Sciences Department, Federal University of Amapá, Macapá, Brazil.
| | - Federica Facchin
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
| | - Carlo Ventura
- National Laboratory of Molecular Biology and Stem Cell Engineering, Eldor Lab, Istituto Nazionale di Biostrutture e Biosistemi (INBB), Innovation Accelerators, CNR, Bologna 40129, Italy.
| | - Claudio Fozza
- Blood Diseases Department of Clinical and Experimental Medicine University of Sassari, 07100 Sassari, Italy.
| | - Margherita Maioli
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; Consorzio Interuniversitario "Istituto Nazionale Biostrutture e Biosistemi" (INBB), Viale delle Medaglie d'Oro 305, 00136, Roma (RM); Center for Developmental Biology and Reprogramming (CEDEBIOR), Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/B, 07100 Sassari, Italy.
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10
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Yang L, Chen Y, Liu N, Lu Y, Ma W, Yang Z, Gan W, Li D. CircMET promotes tumor proliferation by enhancing CDKN2A mRNA decay and upregulating SMAD3. Mol Cancer 2022; 21:23. [PMID: 35042525 PMCID: PMC8764797 DOI: 10.1186/s12943-022-01497-w] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 01/03/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Functions of CircMET (hsa_circ_0082002) which is a circular RNA and derived from MET gene remain understood incompletely. In the present study, Xp11.2 translocation/NONO-TFE3 fusion renal cell carcinoma (NONO-TFE3 tRCC) with up-regulated CircMET was employed to investigate its mechanism in cancer progression and post-transcriptional regulation. METHODS FISH and real-time PCR were performed to explore the expression and localization circMET in NONO-TFE3 tRCC tissues and cells. The functions of circMET in tRCC were investigated by proliferation analysis, EdU staining, colony and sphere formation assay. The regulatory mechanisms among circMET, CDKN2A and SMAD3 were investigated by luciferase assay, RNA immunoprecipitation, RNA pulldown and targeted RNA demethylation system. RESULTS The expression of circMET was upregulated by NONO-TFE3 fusion in NONO-TFE3 tRCC tissues and cells, and overexpression of circMET significantly promoted the growth of NONO-TFE3 tRCC. Mechanistic studies revealed that circMET was delivered to cytosol by YTHDC1 in N6-methyladenosine (m6A)-depend manner. CircMET enhances mRNA decay of CDKN2A by direct interaction and recruitment of YTHDF2. Meanwhile, circMET competitively absorbed miR-1197 and prevented those from SMAD3 mRNA. CONCLUSIONS CircMET promotes the development of NONO-TFE3 tRCC, and the regulation to both CDKN2A and SMAD3 of circMET was revealed. CircMET has the potential to serve as a novel target for the molecular therapy of NONO-TFE3 tRCC as well as the other cancer with high-expressing circMET.
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Affiliation(s)
- Lei Yang
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China
| | - Yi Chen
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China
| | - Ning Liu
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China
| | - Yanwen Lu
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China
| | - Wenliang Ma
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China
| | - Zhenhao Yang
- Department of Urology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210008, Jiangsu, China
| | - Weidong Gan
- Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, Jiangsu, China.
| | - Dongmei Li
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, Jiangsu, China. .,Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, Jiangsu, China.
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11
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Chen Z, Guo Y, Zhao D, Zou Q, Yu F, Zhang L, Xu L. Comprehensive Analysis Revealed that CDKN2A is a Biomarker for Immune Infiltrates in Multiple Cancers. Front Cell Dev Biol 2022; 9:808208. [PMID: 35004697 PMCID: PMC8733648 DOI: 10.3389/fcell.2021.808208] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 12/06/2021] [Indexed: 01/22/2023] Open
Abstract
The CDKN2A (cyclin dependent kinase inhibitor 2A/multiple tumor suppressor 1) gene, also known as the P16 gene, encodes multiple tumor suppressor 1 (MTS1), which belongs to the INK4 family. In tumor tissue, CDKN2A has a high expression level compared with normal tissue and reflects prognosis in tumor patients. Our research targeted the analysis of CDKN2A expression in 33 tumors and clinical parameters, patient prognosis and tumor immunity roles. The CDKN2A expression level was significantly correlated with the tumor mutation burden (TMB) in 10 tumors, and the expression of CDKN2A was also correlated with MSI (microsatellite instability) in 10 tumors. CDKN2A expression was associated with infiltrating lymphocyte (TIL) levels in 22 pancancers, thus suggesting that CDKN2A expression is associated with tumor immunity. Enrichment analysis indicated that CDKN2A expression was involved in natural killer cell-mediated cytotoxicity pathways, antigen processing and presentation, olfactory transduction pathways, and regulation of the autophagy pathway in multiple cancers. CDKN2A was significantly associated with several immune cell infiltrates in pantumors. CDKN2A may serve as a promising prognostic biomarker and is associated with immune infiltrates across cancers.
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Affiliation(s)
- Zheng Chen
- Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, Chengdu, China.,School of Applied Chemistry and Biological Technology, Shenzhen Polytechnic, Shenzhen, China
| | - Yingjie Guo
- Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, Chengdu, China.,School of Electronic and Communication Engineering, Shenzhen Polytechnic, Shenzhen, China
| | - Da Zhao
- Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, Chengdu, China.,School of Applied Chemistry and Biological Technology, Shenzhen Polytechnic, Shenzhen, China
| | - Quan Zou
- Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, Chengdu, China
| | - Fusheng Yu
- Beidahuang Industry Group General Hospital, Harbin, China
| | - Lijun Zhang
- School of Applied Chemistry and Biological Technology, Shenzhen Polytechnic, Shenzhen, China
| | - Lei Xu
- School of Electronic and Communication Engineering, Shenzhen Polytechnic, Shenzhen, China
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12
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Pillai J, Chincholkar T, Dixit R, Pandey M. A systematic review of proteomic biomarkers in oral squamous cell cancer. World J Surg Oncol 2021; 19:315. [PMID: 34711249 PMCID: PMC8555221 DOI: 10.1186/s12957-021-02423-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/06/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Head and neck squamous cell cancer (HNSCC) is the most common cancer associated with chewing tobacco, in the world. As this is divided in to sites and subsites, it does not make it to top 10 cancers. The most common subsite is the oral cancer. At the time of diagnosis, more than 50% of patients with oral squamous cell cancers (OSCC) had advanced disease, indicating the lack of availability of early detection and risk assessment biomarkers. The new protein biomarker development and discovery will aid in early diagnosis and treatment which lead to targeted treatment and ultimately a good prognosis. METHODS This systematic review was performed as per PRISMA guidelines. All relevant studies assessing characteristics of oral cancer and proteomics were considered for analysis. Only human studies published in English were included, and abstracts, incomplete articles, and cell line or animal studies were excluded. RESULTS A total of 308 articles were found, of which 112 were found to be relevant after exclusion. The present review focuses on techniques of cancer proteomics and discovery of biomarkers using these techniques. The signature of protein expression may be used to predict drug response and clinical course of disease and could be used to individualize therapy with such knowledge. CONCLUSIONS Prospective use of these markers in the clinical setting will enable early detection, prediction of response to treatment, improvement in treatment selection, and early detection of tumor recurrence for disease monitoring. However, most of these markers for OSCC are yet to be validated.
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Affiliation(s)
| | | | - Ruhi Dixit
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India
| | - Manoj Pandey
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221 005, India.
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13
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Ghazi N, Khorasanchi M. Markers associated with malignant transformation of oral lichen planus: A review article. Arch Oral Biol 2021; 127:105158. [PMID: 34022545 DOI: 10.1016/j.archoralbio.2021.105158] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 05/08/2021] [Accepted: 05/10/2021] [Indexed: 11/29/2022]
Abstract
Oral lichen planus (OLP) is one of the autoimmune diseases associated with chronic inflammation that involves several complications including the potential for malignant transformation into oral squamous cell carcinoma. Pathogenesis of OLP are yet to be fully comprehended however, it has been demonstrated that the epithelial cells in OLP lesions are affected by cytotoxic T lymphocytes leading to immunological reactions. Various factors are reported to act as diagnostic markers for predicting and monitoring the cancerous progression. Hence, in this review, we summarize and present the latest studies regarding the predictive markers associated with malignant potential of OLP.
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Affiliation(s)
- Narges Ghazi
- Department of Oral and Maxillofacial Pathology, School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Maryam Khorasanchi
- Student Research Committee, School of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran.
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14
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Pandey P, Ralli M, Dixit A, Agarwal S, Chaturvedi V, Sawhney A, Agarwal R. Assessment of immunohistochemical expression of p16 in head and neck squamous cell carcinoma and their correlation with clinicopathological parameters. J Oral Maxillofac Pathol 2021; 25:74-81. [PMID: 34349415 PMCID: PMC8272494 DOI: 10.4103/jomfp.jomfp_252_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 10/27/2020] [Accepted: 01/07/2021] [Indexed: 11/05/2022] Open
Abstract
Introduction: Oral squamous cell carcinoma is a major cause of death throughout the developed world. It is associated with tobacco chewing, paan chewing and alcohol consumption. Human papillomavirus (HPV) type 16 has also been suggested to play a role in the etiology of head-and-neck squamous cell carcinoma (HNSCC). p16 expression is now being used as a surrogate marker of HPV infection in squamous cell carcinoma. Materials and Methods: In this cross-sectional observational study, a total of 100 cases of HNSCC were taken. p16 expression was determined by immunohistochemical (IHC) staining and correlated with clinicopathological parameters. The obtained results were analyzed and evaluated using Chi-square test, value of P < 0.05 was taken significant. Results: P16 was positive in 60% of cases. A statistically significant direct association was observed between p16 with age, site of the tumor, abnormal sexual habits and lymph node involvement. Conclusion: IHC expression of p16 can be used as a surrogate marker of HPV. Study of p16 expression may provide clinicians with more exact information in order to evaluate tumor aggressiveness, treatment modalities and can provide support for vaccination program in a high-risk group.
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Affiliation(s)
- Pinki Pandey
- Department of Pathology, Uttar Pradesh University of Medical Sciences, Etawah, Uttar Pradesh, India
| | - Megha Ralli
- Department of Pathology, Maharaja Suhel Dev Autonomous State Medical College and Mahrishi Balark Hospital, Bahraich, Uttar Pradesh, India
| | - Alok Dixit
- Department of Clinical Pharmacology, Uttar Pradesh University of Medical Sciences, Etawah, Uttar Pradesh, India
| | - Savita Agarwal
- Department of Pathology, Uttar Pradesh University of Medical Sciences, Etawah, Uttar Pradesh, India
| | - Vineet Chaturvedi
- Department of Pathology, Uttar Pradesh University of Medical Sciences, Etawah, Uttar Pradesh, India
| | - Anshul Sawhney
- Department of Dentistry, Maharaja Suhel Dev Autonomous State Medical College and Mahrishi Balark Hospital, Bahraich, Uttar Pradesh, India
| | - Roopak Agarwal
- Department of Pathology, Uttar Pradesh University of Medical Sciences, Etawah, Uttar Pradesh, India
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15
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Hier J, Vachon O, Bernstein A, Ibrahim I, Mlynarek A, Hier M, Alaoui-Jamali MA, Maschietto M, da Silva SD. Portrait of DNA methylated genes predictive of poor prognosis in head and neck cancer and the implication for targeted therapy. Sci Rep 2021; 11:10012. [PMID: 33976322 PMCID: PMC8113272 DOI: 10.1038/s41598-021-89476-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 04/23/2021] [Indexed: 12/31/2022] Open
Abstract
In addition to chronic infection with human papilloma virus (HPV) and exposure to environmental carcinogens, genetic and epigenetic factors act as major risk factors for head and neck cancer (HNC) development and progression. Here, we conducted a systematic review in order to assess whether DNA hypermethylated genes are predictive of high risk of developing HNC and/or impact on survival and outcomes in non-HPV/non-tobacco/non-alcohol associated HNC. We identified 85 studies covering 32,187 subjects where the relationship between DNA methylation, risk factors and survival outcomes were addressed. Changes in DNA hypermethylation were identified for 120 genes. Interactome analysis revealed enrichment in complex regulatory pathways that coordinate cell cycle progression (CCNA1, SFN, ATM, GADD45A, CDK2NA, TP53, RB1 and RASSF1). However, not all these genes showed significant statistical association with alcohol consumption, tobacco and/or HPV infection in the multivariate analysis. Genes with the most robust HNC risk association included TIMP3, DCC, DAPK, CDH1, CCNA1, MGMT, P16, MINT31, CD44, RARβ. From these candidates, we further validated CD44 at translational level in an independent cohort of 100 patients with tongue cancer followed-up beyond 10 years. CD44 expression was associated with high-risk of tumor recurrence and metastasis (P = 0.01) in HPV-cases. In summary, genes regulated by methylation play a modulatory function in HNC susceptibility and it represent a critical therapeutic target to manage patients with advanced disease.
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Affiliation(s)
- Jessica Hier
- Department of Otolaryngology-Head and Neck Surgery, Lady Davis Institute for Medical Research and Segal Cancer Centre, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Côte Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada
| | - Olivia Vachon
- Department of Otolaryngology-Head and Neck Surgery, Lady Davis Institute for Medical Research and Segal Cancer Centre, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Côte Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada
| | - Allison Bernstein
- Department of Otolaryngology-Head and Neck Surgery, Lady Davis Institute for Medical Research and Segal Cancer Centre, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Côte Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada
| | - Iman Ibrahim
- Department of Otolaryngology-Head and Neck Surgery, Lady Davis Institute for Medical Research and Segal Cancer Centre, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Côte Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada
| | - Alex Mlynarek
- Department of Otolaryngology-Head and Neck Surgery, Lady Davis Institute for Medical Research and Segal Cancer Centre, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Côte Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada
| | - Michael Hier
- Department of Otolaryngology-Head and Neck Surgery, Lady Davis Institute for Medical Research and Segal Cancer Centre, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Côte Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada
| | - Moulay A Alaoui-Jamali
- Segal Cancer Centre of the Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Mariana Maschietto
- Department of Structural and Functional Biology, Institute of Biology, Universidade Estadual de Campinas (UNICAMP) and Boldrini Children's Center, Campinas, Sao Paulo, Brazil
| | - Sabrina Daniela da Silva
- Department of Otolaryngology-Head and Neck Surgery, Lady Davis Institute for Medical Research and Segal Cancer Centre, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Côte Ste-Catherine Road, Montreal, QC, H3T 1E2, Canada. .,Segal Cancer Centre of the Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada.
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16
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Senescence in polyploid giant cancer cells: A road that leads to chemoresistance. Cytokine Growth Factor Rev 2020; 52:68-75. [DOI: 10.1016/j.cytogfr.2019.11.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 11/11/2019] [Accepted: 11/14/2019] [Indexed: 01/07/2023]
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17
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Kang HJ, Kim J, Cho SH, Park SJ, Yoo HS, Kang IC. Inhibitory Effects of HangAmDan-B1 (HAD-B1) Combined With Afatinib on H1975 Lung Cancer Cell-Bearing Mice. Integr Cancer Ther 2019; 18:1534735419830765. [PMID: 30866688 PMCID: PMC6419252 DOI: 10.1177/1534735419830765] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Epidermal growth factor receptor mutation-positive non–small cell lung cancer is cared for mainly by target therapeutics in the clinical treatment at present. We investigated the antitumor effect of HangAmDan-B1 (HAD-B1) combined with afatinib on H1975 (L858R/T790M double mutation) lung cancer cells. The combined treatment of HAD-B1 with afatinib inhibited the proliferation of H1975 cells in a dose-dependent manner compared with the treatment of afatinib or HAD-B1 alone. The combined treatment group significantly induced early apoptosis and cell cycle arrest of the cells compared with afatinib- or HAD-B1-treated control group. Profile analysis of cell cycle proteins in H1975 cells treated with the combination of HAD-B1 and afatinib using InnoPharmaScreen antibody microarray showed downregulation of pERK1/2 and upregulation of p16 in the cells. In vivo tumor growth assay in xenograft animal model of human H1975 lung cancer cells revealed that the mean tumor volume in the group treated with the combination of HAD-B1 and afatinib showed a significant reduction compared with the control groups.
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Affiliation(s)
- Hwa Jeong Kang
- 1 Hoseo University, Asan, Chungcheongnam-do, Republic of Korea
| | - Jeehye Kim
- 2 Dunsan Oriental Medical Hospital of Daejeon University, Daejeon, Chungcheongnam-do, Republic of Korea
| | - Seong Hyeok Cho
- 1 Hoseo University, Asan, Chungcheongnam-do, Republic of Korea
| | - So-Jung Park
- 2 Dunsan Oriental Medical Hospital of Daejeon University, Daejeon, Chungcheongnam-do, Republic of Korea
| | - Hwa-Seung Yoo
- 2 Dunsan Oriental Medical Hospital of Daejeon University, Daejeon, Chungcheongnam-do, Republic of Korea
| | - In-Cheol Kang
- 1 Hoseo University, Asan, Chungcheongnam-do, Republic of Korea.,3 InnoPharmaScreen Inc, Asan, Chungcheongnam-do, Republic of Korea
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18
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Rassy E, Nicolai P, Pavlidis N. Comprehensive management of HPV‐related squamous cell carcinoma of the head and neck of unknown primary. Head Neck 2019; 41:3700-3711. [DOI: 10.1002/hed.25858] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 04/09/2019] [Accepted: 06/12/2019] [Indexed: 01/19/2023] Open
Affiliation(s)
- Elie Rassy
- Department of Medical OncologyInstitut Gustave Roussy Villejuif France
- Department of Medical OncologyHotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University Beirut Lebanon
| | - Piero Nicolai
- Department of OtorhinolaryngologyHead and Neck Surgery, University of Brescia Brescia Italy
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19
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Liyanage C, Wathupola A, Muraleetharan S, Perera K, Punyadeera C, Udagama P. Promoter Hypermethylation of Tumor-Suppressor Genes p16INK4a, RASSF1A, TIMP3, and PCQAP/MED15 in Salivary DNA as a Quadruple Biomarker Panel for Early Detection of Oral and Oropharyngeal Cancers. Biomolecules 2019; 9:biom9040148. [PMID: 31013839 PMCID: PMC6523930 DOI: 10.3390/biom9040148] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 04/07/2019] [Accepted: 04/08/2019] [Indexed: 01/01/2023] Open
Abstract
Silencing of tumor-suppressor genes (TSGs) by DNA promoter hypermethylation is an early event in carcinogenesis; hence, TSGs may serve as early tumor biomarkers. We determined the promoter methylation levels of p16INK4a, RASSF1A, TIMP3, and PCQAP/MED15 TSGs in salivary DNA from oral cancer (OC) and oropharyngeal cancer (OPC) patients, using methylation-specific PCR coupled with densitometry analysis. We assessed the association between DNA methylation of individual TSGs with OC and OPC risk factors. The performance and the clinical validity of this quadruple-methylation marker panel were evaluated in discriminating OC and OPC patients from healthy controls using the CombiROC web tool. Our study reports that RASSF1A, TIMP3, and PCQAP/MED15 TSGs were significantly hypermethylated in OC and OPC cases compared to healthy controls. DNA methylation levels of TSGs were significantly augmented by smoking, alcohol use, and betel quid chewing, indicating the fact that frequent exposure to risk factors may drive oral and oropharyngeal carcinogenesis through TSG promoter hypermethylation. Also, this quadruple-methylation marker panel of p16INK4a, RASSF1A, TIMP3, and PCQAP/MED15 TSGs demonstrated excellent diagnostic accuracy in the early detection of OC at 91.7% sensitivity and 92.3% specificity and of OPC at 99.8% sensitivity and 92.1% specificity from healthy controls.
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Affiliation(s)
- Chamikara Liyanage
- Department of Zoology and Environment Sciences, University of Colombo, Colombo 03 00300, Sri Lanka.
| | - Asanga Wathupola
- Department of Zoology and Environment Sciences, University of Colombo, Colombo 03 00300, Sri Lanka.
| | - Sanjayan Muraleetharan
- Department of Zoology and Environment Sciences, University of Colombo, Colombo 03 00300, Sri Lanka.
| | - Kanthi Perera
- National Cancer Institute of Sri Lanka, Maharagama, 10280, Sri Lanka.
| | - Chamindie Punyadeera
- The School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, QLD 4059, Australia.
- Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane, QLD 4102, Australia.
| | - Preethi Udagama
- Department of Zoology and Environment Sciences, University of Colombo, Colombo 03 00300, Sri Lanka.
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20
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"Expression of p16 in oral leukoplakia and oral squamous cell carcinoma and correlation of its expression with individual atypical features". J Oral Biol Craniofac Res 2019; 9:156-160. [PMID: 30963022 DOI: 10.1016/j.jobcr.2019.03.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 03/04/2019] [Accepted: 03/06/2019] [Indexed: 11/20/2022] Open
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21
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Allameh A, Moazeni-Roodi A, Harirchi I, Ravanshad M, Motiee-Langroudi M, Garajei A, Hamidavi A, Mesbah-Namin SA. Promoter DNA Methylation and mRNA Expression Level of p16 Gene in Oral Squamous Cell Carcinoma: Correlation with Clinicopathological Characteristics. Pathol Oncol Res 2018; 25:1535-1543. [PMID: 30511108 DOI: 10.1007/s12253-018-0542-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 11/14/2018] [Indexed: 12/20/2022]
Abstract
The aim of this study was to investigate the relationship between p16 methylation and its expression in oral squamous cell carcinoma (OSCC). Also the contribution of clinicopathological factors, HPV infection and smoking in p16 expression and promoter methylation has been investigated. In this study 67 consecutive OSCC patients and 59 normal individuals were enrolled. All patients were candidates for surgery of oral cavity and fresh tumor biopsies were collected and processed for DNA and RNA extraction. Normal gingival tissues were collected from individuals referred to dentistry clinic and considered as controls. All the cases and controls were checked for HPV infection and then promoter methylation and expression of p16 gene were determined using Methylation-specific PCR (MSP) and real-time PCR (QPCR), respectively. Methylation of p16 in tumors and normal tissues were 59.7 and 38.9%, respectively. Most of hypermethylated samples (>82%) were in high grades. P16 methylation was comparable in HPV+ and HPV- patients or smokers. P16 was overexpressed (~3 fold; p = 0.044) in HPV+ tumors, but it was significantly down-regulated in smoker patients (40% of all tumors). Comparison of P16 expression in OSCC tumors with different degrees of promoter methylation further suggest the relationship of methylation rate and down-regulation of P16 expression. The p16 methylation and expression was differentially affected in patients with HPV infection and the smoker cases. Regardless of the influence of environmental factors, it appears that P16 status is useful for classifying patients with OSCC and for influencing treatment strategies in accordance with this classification. Moreover, targeting the upregulation of p16 could be a promising therapeutic option.
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Affiliation(s)
- Abdolamir Allameh
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Islamic Republic of Iran.
| | - Abdolkarim Moazeni-Roodi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Islamic Republic of Iran.,Department of Clinical Biochemistry, Iranshahr University of Medical Sciences, Iranshahr, Iran
| | - Iraj Harirchi
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Mehrdad Ravanshad
- Department of Medical Virology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Islamic Republic of Iran
| | - Maziar Motiee-Langroudi
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Ata Garajei
- Cancer Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.,Department of Oral and Maxillofacial Surgery, School of Dentistry and Department of Head and Neck Surgical Oncology and Reconstructive Surgery, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Azin Hamidavi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Islamic Republic of Iran
| | - Seyed Alireza Mesbah-Namin
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Islamic Republic of Iran
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Primary Mucosal Melanoma of the Stomach. Case Rep Gastrointest Med 2018; 2018:6040693. [PMID: 30159179 PMCID: PMC6109490 DOI: 10.1155/2018/6040693] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 06/17/2018] [Accepted: 07/16/2018] [Indexed: 12/12/2022] Open
Abstract
Considered to be rare, mucosal melanomas are rare type of melanoma that are found on mucosal surfaces and are primary or metastatic in origin. We report a case of a 66-year-old Hispanic female who presented with vague abdominal pain and upon further endoscopic work-up revealed 2 gastric lesions. Endoscopic biopsy results revealed gastric melanoma in the distal lesion. A PET/CT scan indicated it to be suspicious for the primary site of metastasis but was ultimately diagnosed as a benign nevus on biopsy. An extensive clinical exam showed no other probable sites of origin. The patient underwent a subtotal Billroth II gastrectomy and enterostomy tube placement for temporary feeding. Primary melanoma of the stomach is an exceptionally rare occurrence with limited cases that can be accounted for in literature; thus we report this case for review.
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23
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Rosa EA, Hurtado-Puerto AM, Falcão DP, Brietzke AP, De Almeida Prado Franceschi LE, Cavalcanti Neto FF, Tiziane V, Carneiro FP, Kogawa EM, Moreno H, Amorim RFB. Oral lichen planus and malignant transformation: The role of p16, Ki-67, Bub-3 and SOX4 in assessing precancerous potential. Exp Ther Med 2018; 15:4157-4166. [PMID: 29731815 PMCID: PMC5920964 DOI: 10.3892/etm.2018.5971] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 12/08/2017] [Indexed: 12/25/2022] Open
Abstract
The association of oral lichen planus (OLP) lesions with malignant transformation risk has remained a controversial topic and is of clinical importance. Therefore, the present study evaluated the expression levels of p16, Ki-67, budding uninhibited by benzimidazoles 3 (Bub-3) and sex-determining region Y-related high mobility group box 4 (SOX4), and their roles as precancerous biomarkers in OLP. A retrospective study was performed, in which tissue blocks of OLP, oral dysplasia (OD), cutaneous lichen planus (CLP) and oral fibrous hyperplasia (OFH) were used (n=120). A positivity index (PI) for p16, BUB3, Ki-67 and SOX4 expression was calculated in each group. The PI for p16 was 20.65% for OLP, 7.85% for OD, 86.59% for CLP and 11.8% for OFH, and the difference between these groups was statistically significant (P<0.001). PIs of Ki-67 were indicated as 11.6% for OLP, 14.4% for OD, 8.24% for CLP and 5.5% for OFH, and a statistically significant difference was observed between the groups (P<0.001). Notably, the expression levels of BUB3 were not statistically different among groups. The highest expression levels of SOX4 were identified in CLP (P<0.001 vs. OLP/CLP; P=0,001 vs. CLP/OD). The determined expression levels of p16 and Ki-67 suggest that specific OLP lesions may have an intermediate malignant potential and should be carefully followed up. The intense SOX4 staining in CLP indicated a different proliferation pattern of epithelium compared with oral mucosa cells. These findings suggest that SOX4 expression may also be associated with the different clinical courses of OLP and CLP.
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Affiliation(s)
- Eduardo Augusto Rosa
- Post-Graduation Program in Medical Sciences, Department of Pathology, School of Medicine, University of Brasília, Brasília 70910-900, Brazil
| | - Aura Maria Hurtado-Puerto
- Laboratory for Neuropsychiatry and Neuromodulation, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Denise Pinheiro Falcão
- Post-Graduation Program in Medical Sciences, Department of Pathology, School of Medicine, University of Brasília, Brasília 70910-900, Brazil
| | - Aline Patricia Brietzke
- Laboratory of Pain and Neuromodulation at Hospital de Clínicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90035-903, Brazil
| | | | | | - Valdenize Tiziane
- Center for Learning and Research, Brasília Children's Hospital, Brasília 70910-90, Brazil
| | - Fabiana Pirani Carneiro
- Post-Graduation Program in Medical Sciences, Department of Pathology, School of Medicine, University of Brasília, Brasília 70910-900, Brazil
| | - Evelyn Mikaela Kogawa
- Post-Graduation Program in Medical Sciences, Department of Pathology, School of Medicine, University of Brasília, Brasília 70910-900, Brazil
| | - Heitor Moreno
- Laboratory of Cardiovascular Pharmacology, School of Medical Sciences, University of Campinas, Campinas, São Paulo 13083-970, Brazil
| | - Rivadávio Fernandes Batista Amorim
- Post-Graduation Program in Medical Sciences, Department of Pathology, School of Medicine, University of Brasília, Brasília 70910-900, Brazil
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24
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Markers of Oral Lichen Planus Malignant Transformation. DISEASE MARKERS 2018; 2018:1959506. [PMID: 29682099 PMCID: PMC5846459 DOI: 10.1155/2018/1959506] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 01/15/2018] [Indexed: 12/17/2022]
Abstract
Oral lichen planus (OLP) is a chronic inflammatory disease of unknown etiology with significant impact on patients' quality of life. Malignant transformation into oral squamous cell carcinoma (OSCC) is considered as one of the most serious complications of the disease; nevertheless, controversy still persists. Various factors seem to be involved in the progression of malignant transformation; however, the mechanism of this process is not fully understood yet. Molecular alterations detected in OLP samples might represent useful biomarkers for predicting and monitoring the malignant progression. In this review, we discuss various studies which highlight different molecules as ominous predictors of OLP malignant transformation.
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25
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Gribko A, Hahlbrock A, Strieth S, Becker S, Hagemann J, Deichelbohrer M, Hildebrandt A, Habtemichael N, Wünsch D. Disease-relevant signalling-pathways in head and neck cancer: Taspase1's proteolytic activity fine-tunes TFIIA function. Sci Rep 2017; 7:14937. [PMID: 29097782 PMCID: PMC5668323 DOI: 10.1038/s41598-017-14814-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 10/16/2017] [Indexed: 12/23/2022] Open
Abstract
Head and neck cancer (HNC) is the seventh most common malignancy in the world and its prevailing form, the head and neck squamous cell carcinoma (HNSCC), is characterized as aggressive and invasive cancer type. The transcription factor II A (TFIIA), initially described as general regulator of RNA polymerase II-dependent transcription, is part of complex transcriptional networks also controlling mammalian head morphogenesis. Posttranslational cleavage of the TFIIA precursor by the oncologically relevant protease Taspase1 is crucial in this process. In contrast, the relevance of Taspase1-mediated TFIIA cleavage during oncogenesis of HNSCC is not characterized yet. Here, we performed genome-wide expression profiling of HNSCC which revealed significant downregulation of the TFIIA downstream target CDKN2A. To identify potential regulatory mechanisms of TFIIA on cellular level, we characterized nuclear-cytoplasmic transport and Taspase1-mediated cleavage of TFIIA variants. Unexpectedly, we identified an evolutionary conserved nuclear export signal (NES) counteracting nuclear localization and thus, transcriptional activity of TFIIA. Notably, proteolytic processing of TFIIA by Taspase1 was found to mask the NES, thereby promoting nuclear localization and transcriptional activation of TFIIA target genes, such as CDKN2A. Collectively, we here describe a hitherto unknown mechanism how cellular localization and Taspase1 cleavage fine-tunes transcriptional activity of TFIIA in HNSCC.
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Affiliation(s)
- Alena Gribko
- Department of Otorhinolaryngology, Molecular and Cellular Oncology, University Hospital of Mainz, Langenbeckstrasse 1, Mainz, 55101, Germany
| | - Angelina Hahlbrock
- Department of Otorhinolaryngology, Molecular and Cellular Oncology, University Hospital of Mainz, Langenbeckstrasse 1, Mainz, 55101, Germany
| | - Sebastian Strieth
- Department of Otorhinolaryngology, Molecular and Cellular Oncology, University Hospital of Mainz, Langenbeckstrasse 1, Mainz, 55101, Germany
| | - Sven Becker
- Department of Otorhinolaryngology, Molecular and Cellular Oncology, University Hospital of Mainz, Langenbeckstrasse 1, Mainz, 55101, Germany
| | - Jan Hagemann
- Department of Otorhinolaryngology, Molecular and Cellular Oncology, University Hospital of Mainz, Langenbeckstrasse 1, Mainz, 55101, Germany
| | - Max Deichelbohrer
- Department of Otorhinolaryngology, Molecular and Cellular Oncology, University Hospital of Mainz, Langenbeckstrasse 1, Mainz, 55101, Germany
| | - Andreas Hildebrandt
- Scientific Computing and Bioinformatics, Johannes Gutenberg University, Staudingerweg 9, Mainz, 55128, Germany
| | - Negusse Habtemichael
- Department of Otorhinolaryngology, Molecular and Cellular Oncology, University Hospital of Mainz, Langenbeckstrasse 1, Mainz, 55101, Germany
| | - D Wünsch
- Department of Otorhinolaryngology, Molecular and Cellular Oncology, University Hospital of Mainz, Langenbeckstrasse 1, Mainz, 55101, Germany.
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26
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Khatami F, Larijani B, Heshmat R, Keshtkar A, Mohammadamoli M, Teimoori-Toolabi L, Nasiri S, Tavangar SM. Meta-analysis of promoter methylation in eight tumor-suppressor genes and its association with the risk of thyroid cancer. PLoS One 2017; 12:e0184892. [PMID: 28926589 PMCID: PMC5605048 DOI: 10.1371/journal.pone.0184892] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Accepted: 09/03/2017] [Indexed: 01/11/2023] Open
Abstract
Promoter methylation in a number of tumor-suppressor genes (TSGs) can play crucial roles in the development of thyroid carcinogenesis. The focus of the current meta-analysis was to determine the impact of promoter methylation of eight selected candidate TSGs on thyroid cancer and to identify the most important molecules in this carcinogenesis pathway. A comprehensive search was performed using Pub Med, Scopus, and ISI Web of Knowledge databases, and eligible studies were included. The methodological quality of the included studies was evaluated according to the Newcastle Ottawa scale table and pooled odds ratios (ORs); 95% confidence intervals (CIs) were used to estimate the strength of the associations with Stata 12.0 software. Egger's and Begg's tests were applied to detect publication bias, in addition to the "Metatrim" method. A total of 55 articles were selected, and 135 genes with altered promoter methylation were found. Finally, we included eight TSGs that were found in more than four studies (RASSF1, TSHR, PTEN, SLC5A, DAPK, P16, RARβ2, and CDH1). The order of the pooled ORs for these eight TSGs from more to less significant was CDH1 (OR = 6.73), SLC5 (OR = 6.15), RASSF1 (OR = 4.16), PTEN (OR = 3.61), DAPK (OR = 3.51), P16 (OR = 3.31), TSHR (OR = 2.93), and RARβ2 (OR = 1.50). Analyses of publication bias and sensitivity confirmed that there was very little bias. Thus, our findings showed that CDH1 and SCL5A8 genes were associated with the risk of thyroid tumor genesis.
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Affiliation(s)
- Fatemeh Khatami
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Heshmat
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbasali Keshtkar
- Department of Health Sciences Education Development, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahsa Mohammadamoli
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Shirzad Nasiri
- Department of Surgery, Tehran University of Medical Sciences, Shariati Hospital, Tehran, Iran
| | - Seyed Mohammad Tavangar
- Department of Pathology, Dr. Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
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27
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Walline HM, Carey TE, Goudsmit CM, Bellile EL, D'Souza G, Peterson LA, McHugh JB, Pai SI, Lee JJ, Shin DM, Ferris RL. High-Risk HPV, Biomarkers, and Outcome in Matched Cohorts of Head and Neck Cancer Patients Positive and Negative for HIV. Mol Cancer Res 2016; 15:179-188. [PMID: 27899422 DOI: 10.1158/1541-7786.mcr-16-0255] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 09/28/2016] [Accepted: 11/07/2016] [Indexed: 01/27/2023]
Abstract
In this study, high-risk HPV (hrHPV) incidence, prognostic biomarkers, and outcome were assessed in HIV-positive (case) and HIV-negative (control) patients with head and neck squamous cell cancer (HNSCC). HIV-positive cases were matched to controls by tumor site, sex, and age at cancer diagnosis. A tissue microarray (TMA) was constructed and DNA isolated from tumor tissue. MultiPlex-PCR MassArray, L1-PCR, and in situ hybridization were used to assess hrHPV. TMA sections were stained for p16ink4a, TP53, RB, CCND1, EGFR, and scored for intensity and proportion of positive tumor cells. The HNSCC cohort included 41 HIV-positive cases and 41 HIV-negative controls. Tumors from 11 of 40 (28%) cases, and 10 of 41 (24%) controls contained hrHPV. p16 expression, indicative of E7 oncogene activity, was present in 10 of 11 HPV-positive cases and 7 of 10 HPV-positive controls. Low p16 and high TP53 expression in some HPV-positive tumors suggested HPV-independent tumorigenesis. Survival did not differ in cases and controls. RB expression was significantly associated with poor survival (P = 0.01). High TP53 expression exhibited a trend for poorer survival (P = 0.12), but among cases, association with poor survival reached statistical significance (P = 0.04). The proportion of HPV-positive tumors was similar, but the heterogeneity of HPV types was higher in the HIV-positive cases than in HIV-negative controls. High RB expression predicted poor survival, and high TP53 expression was associated with poorer survival in the HIV-positive cases but not HIV-negative controls. IMPLICATIONS HIV infection did not increase risk of death from HNSCC, and HPV-positive tumors continued to be associated with a significantly improved survival, independent of HIV status. Mol Cancer Res; 15(2); 179-88. ©2016 AACR.
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Affiliation(s)
- Heather M Walline
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.,Cancer Biology Training Program, University of Michigan, Ann Arbor, Michigan
| | - Thomas E Carey
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan.
| | - Christine M Goudsmit
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, Michigan
| | - Emily L Bellile
- Biostatistics Core, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan
| | - Gypsyamber D'Souza
- Department of Epidemiology, School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | - Lisa A Peterson
- Head and Neck SPORE, University of Michigan Cancer Center, Ann Arbor, Michigan
| | - Jonathan B McHugh
- Department of Pathology, University of Michigan, Ann Arbor, Michigan
| | - Sara I Pai
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, Baltimore, Maryland
| | - J Jack Lee
- Department of Biostatistics, MD Anderson Cancer Center, Houston, Texas
| | - Dong M Shin
- Department of Medicine, Medical Oncology Winship Cancer Center, Emory University, Atlanta, Georgia
| | - Robert L Ferris
- Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
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28
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Abstract
Oral squamous cell carcinoma is the most common neoplasia of the mouth. Downregulation of p16(INK4a) (a cyclin-dependent kinase inhibitor) has been reported for mouth cancer and it is believed that its inactivation is an early event in oral carcinogenesis. The goal of this article is to quantitatively report expression of p16(INK4a) and the state of methylation in oral squamous cell carcinoma, and evaluate its relationship with the clinical and prognostic factors, in addition to setting out a multivariate model that predicts survival. The mean expression of p16(INK4a) was 7.70 (SD=14.07) (F=0.894; P=0.449). According to the semiquantitative analysis, there were statistically significant differences, where 19 cases were negative (<2 %), 11 at initial stages, and 8 at advanced stages (χ(2)=6.016; P<0.05). The methylation of p16(INK4a) was not associated with any of the clinical or pathologic variables. Kaplan-Meier curve showed a better survival for patients in initial stages (40.72 mo) compared to those in advanced stages (28.6 mo) (P<0.01). Survival was also reduced in a statistically significant manner in patients with any degree of dysplasia in the adjacent margin (P<0.05). During univariate Cox regression analysis, it was observed that individuals with relapse had a higher risk (almost 9 times higher) [P<0.001; hazard ratio=8.91; 95% confidence interval (CI), 4.18-19.02]. During the Cox multivariate analysis for each unit of decrease in p16(INK4a), the risk increased by 1.06) (P<0.05; hazard ratio=0.94; 95% CI, 0.89-1.00). p16(INK4a) expression is reduced with advancing tumor stage and its gene silencing is associated with an increased risk of death.
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29
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Beck TN, Kaczmar J, Handorf E, Nikonova A, Dubyk C, Peri S, Lango M, Ridge JA, Serebriiskii IG, Burtness B, Golemis EA, Mehra R. Phospho-T356RB1 predicts survival in HPV-negative squamous cell carcinoma of the head and neck. Oncotarget 2016; 6:18863-74. [PMID: 26265441 PMCID: PMC4662460 DOI: 10.18632/oncotarget.4321] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 05/22/2015] [Indexed: 11/25/2022] Open
Abstract
Locally advanced squamous cell carcinoma of the head and neck (SCCHN) that is not associated with human papillomavirus (HPV) has a poor prognosis in contrast to HPV-positive disease. To better understand the importance of RB1 activity in HPV-negative SCCHN, we investigated the prognostic value of inhibitory CDK4/6 phosphorylation of RB1 on threonine 356 (T356) in archival HPV-negative tumor specimens from patients who underwent surgical resection and adjuvant radiation. We benchmarked pT356RB1 to total RB1, Ki67, pT202/Y204ERK1/2, and TP53, as quantified by automatic quantitative analysis (AQUA), and correlated protein expression with tumor stage and grade. High expression of pT356RB1 but not total RB1 predicted reduced overall survival (OS; P = 0.0295), indicating the potential relevance of post-translational phosphorylation. Paired analysis of The Cancer Genome Atlas (TCGA) data for regulators of this RB1 phosphorylation identified loss or truncating mutation of negative regulator CDKN2A (p16) and elevated expression of the CDK4/6 activator CCND1 (cyclin D) as also predicting poor survival. Given that CDK4/6 inhibitors have been most effective in the context of functional RB1 and low expression or deletion of p16 in other tumor types, these data suggest such agents may merit evaluation in HPV-negative SCCHN, specifically in cases associated with high pT356RB1.
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Affiliation(s)
- Tim N Beck
- Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.,Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA, USA
| | - John Kaczmar
- Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.,Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Elizabeth Handorf
- Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Anna Nikonova
- Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Cara Dubyk
- Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Suraj Peri
- Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Miriam Lango
- Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - John A Ridge
- Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Ilya G Serebriiskii
- Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.,Department of Biochemistry, Kazan Federal University, Kazan, Russia
| | - Barbara Burtness
- Department of Internal Medicine, Yale University School of Medicine and Yale Cancer Center, New Haven, CT, USA
| | - Erica A Golemis
- Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.,Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA, USA
| | - Ranee Mehra
- Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.,Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
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30
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Nwanze J, Cohen C, Schmitt AC, Siddiqui MT. β-Catenin Expression in Oropharyngeal Squamous Cell Carcinomas: Comparison and Correlation with p16 and Human Papillomavirus in situ Hybridization. Acta Cytol 2016; 59:479-84. [PMID: 26849661 DOI: 10.1159/000443602] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 12/22/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND The Wnt/β-catenin signaling pathway has been noted to be upregulated in head and neck cancers, including oropharyngeal squamous cell carcinoma (OSCC). This study compared the efficacy of β-catenin immunohistochemistry (IHC), p16 IHC and automated human papillomavirus (HPV) in situ hybridization (ISH) in OSCC. METHODS Sixty-eight OSCCs (48 surgical specimens and 20 fine-needle aspirations) were evaluated. Nuclear staining only of β-catenin was assessed as 0-3+ intensity (relative to controls of benign squamous mucosa). p16 was interpreted as positive if 70% of tumor cells showed brown nuclear and cytoplasmic staining. HPV ISH was interpreted as positive if a minimum of one tumor cell showed brown punctate dot-like nuclear positivity. p16 IHC and HPV ISH were then correlated with β-catenin staining. HPV ISH was used as the gold standard. RESULTS Twenty-five of 48 surgical specimens (52.1%) and 11 of 20 cell blocks (55%) stained positively for β-catenin, making a total of 36 of 68 (52.9%) staining positively for β-catenin, as compared to 61.7% positive for p16 IHC and 70.6% positive by automated HPV ISH, the gold standard method for OSCC diagnosis. x03C7;2 analysis revealed no significant correlation between β-catenin and HPV ISH (p > 0.05) and demonstrated a strong correlation between p16 and HPV ISH (p < 0.05). CONCLUSION β-Catenin IHC is not a sensitive or specific marker of HPV and is unlikely to be a useful adjunct to p16 IHC or HPV ISH in the setting of advanced OSCC. However, as this study focused on samples of advanced OSCC, β-catenin IHC may still find some use in the diagnosis of early-stage OSCC.
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Affiliation(s)
- Julum Nwanze
- Department of Pathology and Laboratory Medicine, Emory University Hospital, Atlanta, Ga., USA
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31
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Yang XY, Miyamoto C, Akasaka T, Izukuri K, Maehata Y, Ikoma T, Ozawa S, Hata RI. Chemokine CXCL14 is a multistep tumor suppressor. J Oral Biosci 2016. [DOI: 10.1016/j.job.2015.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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32
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Sushma PS, Jamil K, Kumar PU, Satyanarayana U, Ramakrishna M, Triveni B. PTEN and p16 genes as epigenetic biomarkers in oral squamous cell carcinoma (OSCC): a study on south Indian population. Tumour Biol 2015; 37:7625-32. [PMID: 26687648 DOI: 10.1007/s13277-015-4648-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 12/14/2015] [Indexed: 11/25/2022] Open
Abstract
Phosphatase and tensin homolog (PTEN) and p16INK4a (p16) genes are tumor suppressor genes, associated with epigenetic alterations. PTEN and p16 promoter hypermethylation is a major epigenetic silencing mechanism leading to cancer. The cooperation between PTEN and p16 in pathogenesis of cancers suggest that their combination might be considered as potential molecular marker for specific subgroups of patients. Hence, the present study aimed to investigate whether PTEN and p16 promoter methylations were involved in oral squamous cell carcinoma (OSCC) in south Indian subjects. DNA methylation quantitative analyses of the two candidate tumor suppressor genes PTEN and p16 were performed by methylation-specific polymerase chain reaction (MSP). Fifty OSCC biopsy samples and their corresponding non-malignant portions as controls were studied comparatively. The methylation status was correlated with the clinical manifestations. Twelve out of 50 patients (24 %) were found to be methylated for PTEN gene, whereas methylation of the p16 gene occurred in 19 out of 50 cases (38 %). A statistically significant result was obtained (P = <0.0001 and 0.017) for both PTEN and p16 genes. PTEN and p16 promoter methylation may be the main mechanism leading to the low expression of PTEN and p16 genes indicating the progress of tumor development. Our data suggest that a low PTEN and p16 expression due to methylation may contribute to the cancer progression and could be useful for prognosis of OSCC. Therefore, analysis of promoter methylation in such genes may provide a biomarker valuable for early detection of oral cancer.
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MESH Headings
- Adult
- Aged
- Biomarkers, Tumor
- Biopsy
- Carcinoma, Squamous Cell/epidemiology
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/pathology
- Cell Transformation, Neoplastic
- Cyclin-Dependent Kinase Inhibitor p16/analysis
- Cyclin-Dependent Kinase Inhibitor p16/physiology
- DNA Methylation
- DNA, Neoplasm/chemistry
- DNA, Neoplasm/genetics
- Early Detection of Cancer
- Female
- Gene Expression Regulation, Neoplastic
- Genes, p16
- Humans
- India/epidemiology
- Male
- Middle Aged
- Models, Biological
- Mouth Neoplasms/epidemiology
- Mouth Neoplasms/genetics
- Mouth Neoplasms/pathology
- PTEN Phosphohydrolase/analysis
- PTEN Phosphohydrolase/genetics
- PTEN Phosphohydrolase/physiology
- Promoter Regions, Genetic/genetics
- Risk Factors
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Affiliation(s)
- P S Sushma
- Department of Pathology, National Institute of Nutrition (ICMR), Hyderabad, Telangana, India
| | - Kaiser Jamil
- Department of Genetics, Bhagwan Mahavir Medical Research Centre, Hyderabad, 500004, Telangana, India.
| | - P Uday Kumar
- Department of Pathology, National Institute of Nutrition (ICMR), Hyderabad, Telangana, India
| | - U Satyanarayana
- Department of Biochemistry, Dr. Pinnamaneni Siddhartha Institute of Medical Sciences, Chinnoutpalli, Gannavaram, A.P, India
| | - M Ramakrishna
- MNJ Institute of Oncology and Regional Cancer Centre, Hyderabad, Telangana, India
| | - B Triveni
- MNJ Institute of Oncology and Regional Cancer Centre, Hyderabad, Telangana, India
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33
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Szentkúti G, Dános K, Brauswetter D, Kiszner G, Krenács T, Csákó L, Répássy G, Tamás L. Correlations between prognosis and regional biomarker profiles in head and neck squamous cell carcinomas. Pathol Oncol Res 2015; 21:643-50. [PMID: 25547827 DOI: 10.1007/s12253-014-9869-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Accepted: 11/06/2014] [Indexed: 10/24/2022]
Abstract
Head and neck squamous cell carcinomas (HNSCC) show diverse clinicopathological features and are mostly linked with poor outcome. In this study, we tested if the expression of tumor growth, cell cycle and basement membrane anchorage related biomarkers allow prognostic and clinicopathological stratification of HNSCC. Archived HNSCC samples from 226 patients included into tissue microarrays (TMA) were tested using immunohistochemistry. Histopathological evaluation and the analysis of immunostaining for EGFR, Ki67, p53, p16(ink4) and Collagen XVII proteins were carried out in digital whole slides. Statistical evaluation was carried out using Pearson's Chi-square test and Kaplan-Meier survival analysis. In the tested cohort, hypopharyngeal cancers had the least favorable, and glottic cancers had the most favorable prognosis. High Ki67 positive tumor cell fractions were associated with significantly worse prognosis and elevated rate of lymph node metastasis. Both Ki67 and EGFR expression correlated significantly with the tumor localization. Ki67 index was the highest in the hypopharyngeal region and it proved to be the lowest in the glottic region. EGFR expression was the highest in the oral cavity and the lowest in the glottic region. The survival rate of patients with p16(ink4)-negative cancer was significantly lower than of those with p16(ink4)-positive disease. A significant inverse correlation was found between histological grade and the prognosis of HNSCC. Our data support that elevated Ki67 positive proliferating cell fractions contribute to the unfavorable prognosis of hypopharyngeal cancers, while glottic cancers have the most favorable prognosis because of the lowest Ki67 expression rate.
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Affiliation(s)
- Gabriella Szentkúti
- Department of Oto-Rhino-Laryngology, Jahn Ferenc South-Pest Hospital, 1st Köves Street, 1204, Budapest, Hungary,
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Association between P16INK4a promoter methylation and HNSCC: a meta-analysis of 21 published studies. PLoS One 2015; 10:e0122302. [PMID: 25835498 PMCID: PMC4383544 DOI: 10.1371/journal.pone.0122302] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 02/19/2015] [Indexed: 01/10/2023] Open
Abstract
Background The p16INK4a is an important tumor suppressor gene (TSG) and aberrant methylation of promoter is known to be a major inactivation mechanism of the tumor suppressor and tumor-related genes. Aberrant TSG methylation was considered an important epigenetic silencing mechanism in the progression of head and neck squamous cell carcinoma (HNSCC). However, some studies have reported differences in the methylation frequencies of P16INK4a promoter between cancer and the corresponding control group. Therefore, we conducted a meta-analysis to better identify the association. Methods PubMed, Ovid, ISI Web of Science, and EMBASE were searched to identify eligible studies to evaluate the association of p16INK4a promoter methylation and HNSCC. Odds ratio (ORs) and 95% confidence intervals (95%CI) were calculated to evaluate the strength of association between p16INK4a promoter methylation and HNSCC. Results A total of twenty-one studies with 1155 cases and 1017 controls were included in the meta-analysis. The frequencies of p16INK4a promoter methylation in the cancer group were significantly higher than those in the control group (cancer group: median: 46.67%, range = 7.84%-95.12%; control group: median: 18.37%, range = 0–83.33%; respectively). The pooled odds ratio was 3.37 (95%CI = 2.32–4.90) in the cancer group versus the corresponding control group under the random-effects model. Conclusion This meta-analysis of 21 published studies identified that aberrant methylation of p16INK4a promoter was found to be significantly associated with HNSCC.
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Ribeiro DR, Alves ÂVF, dos Santos EP, Padilha FF, Gomes MZ, Rabelo AS, Cardoso JC, Massarioli AP, de Alencar SM, de Albuquerque-Júnior RLC. Inhibition of DMBA-induced Oral Squamous Cells Carcinoma Growth by Brazilian Red Propolis in Rodent Model. Basic Clin Pharmacol Toxicol 2015; 117:85-95. [DOI: 10.1111/bcpt.12374] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 12/22/2014] [Indexed: 12/23/2022]
Affiliation(s)
- Danielle R. Ribeiro
- Laboratory of Morphology and Experimental Pathology; Institute of Technology and Research -ITP; Aracaju SE Brazil
| | - Ângela Valéria F. Alves
- Laboratory of Morphology and Experimental Pathology; Institute of Technology and Research -ITP; Aracaju SE Brazil
| | - Esaú P. dos Santos
- Laboratory of Morphology and Experimental Pathology; Institute of Technology and Research -ITP; Aracaju SE Brazil
| | - Francine F. Padilha
- Laboratory of Biomaterials; Institute of Technology and Research -ITP; Aracaju SE Brazil
- Department of Pharmacy; University Tiradentes; Aracaju SE Brazil
| | - Margarete Z. Gomes
- Laboratory of Morphology and Experimental Pathology; Institute of Technology and Research -ITP; Aracaju SE Brazil
| | - Alessandra S. Rabelo
- Laboratory of Biomaterials; Institute of Technology and Research -ITP; Aracaju SE Brazil
- Department of Pharmacy; University Tiradentes; Aracaju SE Brazil
| | - Juliana C. Cardoso
- Laboratory of Biomaterials; Institute of Technology and Research -ITP; Aracaju SE Brazil
- Department of Pharmacy; University Tiradentes; Aracaju SE Brazil
| | - Adna Prado Massarioli
- Department of Agri-Food Industry, Food and Nutrition; ‘Luiz de Queiroz’ College of Agriculture; University of Sao Paulo (USP); Piracicaba SP Brazil
| | - Severino Matias de Alencar
- Department of Agri-Food Industry, Food and Nutrition; ‘Luiz de Queiroz’ College of Agriculture; University of Sao Paulo (USP); Piracicaba SP Brazil
| | - Ricardo Luiz C. de Albuquerque-Júnior
- Laboratory of Morphology and Experimental Pathology; Institute of Technology and Research -ITP; Aracaju SE Brazil
- Department of Odontology; University Tiradentes; Aracaju SE Brazil
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p16INK4 Expression is not associated with human papillomavirus in oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol 2014; 118:694-702. [DOI: 10.1016/j.oooo.2014.09.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Revised: 07/22/2014] [Accepted: 09/03/2014] [Indexed: 01/09/2023]
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Le JM, Squarize CH, Castilho RM. Histone modifications: Targeting head and neck cancer stem cells. World J Stem Cells 2014; 6:511-525. [PMID: 25426249 PMCID: PMC4178252 DOI: 10.4252/wjsc.v6.i5.511] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 09/10/2014] [Accepted: 09/17/2014] [Indexed: 02/06/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and is responsible for a quarter of a million deaths annually. The survival rate for HNSCC patients is poor, showing only minor improvement in the last three decades. Despite new surgical techniques and chemotherapy protocols, tumor resistance to chemotherapy remains a significant challenge for HNSCC patients. Numerous mechanisms underlie chemoresistance, including genetic and epigenetic alterations in cancer cells that may be acquired during treatment and activation of mitogenic signaling pathways, such as nuclear factor kappa-light-chain-enhancer-of activated B cell, that cause reduced apoptosis. In addition to dysfunctional molecular signaling, emerging evidence reveals involvement of cancer stem cells (CSCs) in tumor development and in tumor resistance to chemotherapy and radiotherapy. These observations have sparked interest in understanding the mechanisms involved in the control of CSC function and fate. Post-translational modifications of histones dynamically influence gene expression independent of alterations to the DNA sequence. Recent findings from our group have shown that pharmacological induction of post-translational modifications of tumor histones dynamically modulates CSC plasticity. These findings suggest that a better understanding of the biology of CSCs in response to epigenetic switches and pharmacological inhibitors of histone function may directly translate to the development of a mechanism-based strategy to disrupt CSCs. In this review, we present and discuss current knowledge on epigenetic modifications of HNSCC and CSC response to DNA methylation and histone modifications. In addition, we discuss chromatin modifications and their role in tumor resistance to therapy.
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p16 hypermethylation: A biomarker for increased esophageal cancer susceptibility in high incidence region of North East India. Tumour Biol 2014; 36:1627-42. [DOI: 10.1007/s13277-014-2762-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 10/22/2014] [Indexed: 10/24/2022] Open
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Razzouk S. Translational genomics and head and neck cancer: toward precision medicine. Clin Genet 2014; 86:412-21. [PMID: 25143247 DOI: 10.1111/cge.12487] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Revised: 08/12/2014] [Accepted: 08/18/2014] [Indexed: 12/19/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) comprise a wide spectrum of neoplasms with different tumor biologies, prognosis and response to therapies. Current tumor classification and traditional diagnostic methods (e.g. clinical assessment, histopathology) are limited in their capacity to determine prognosis and clinical decision-making. Despite recent improvements in treatment, the outcome for patients with HNSCC remains poor. Similar to most tumors, several patient-related factors, (e.g. genetics and environment) and disease-related factors (e.g. tumor location, TMN staging) play a significant role on survival. Thus, the problem in defining the prognosis is that the clinical course and response to treatment differ considerably among patients. Such interindividual variability is related to the heterogeneity of the tumor, genetic and epigenetic variations, thus reflecting the interaction of multiple biological components that result in a unique phenotype. Integrative genomics are developed to identify the molecular pathways leading to cancer at the individual level and find novel prognostic markers for HNSCC, hence tailoring a treatment accordingly. Such genetic-based personalized diagnosis allows tumor stratification and implementation of targeted therapy. Modern medicine includes new drugs that disrupt the implicated molecules and their signaling pathways. Here, we summarize the current state of knowledge that elucidates the translation of genetic data into clinical benefit.
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Affiliation(s)
- S Razzouk
- Department of Periodontology and Implant Dentistry, New York University College of Dentistry, New York City, NY; Private practice, Beirut, Lebanon
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40
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Salehinejad J, Sharifi N, Amirchaghmaghi M, Ghazi N, Shakeri MT, Ghazi A. Immunohistochemical expression of p16 protein in oral squamous cell carcinoma and lichen planus. Ann Diagn Pathol 2014; 18:210-3. [DOI: 10.1016/j.anndiagpath.2014.03.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 02/20/2014] [Accepted: 03/28/2014] [Indexed: 10/25/2022]
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Arantes LMRB, de Carvalho AC, Melendez ME, Carvalho AL, Goloni-Bertollo EM. Methylation as a biomarker for head and neck cancer. Oral Oncol 2014; 50:587-92. [PMID: 24656975 DOI: 10.1016/j.oraloncology.2014.02.015] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 02/13/2014] [Accepted: 02/20/2014] [Indexed: 02/08/2023]
Abstract
Head and neck cancer is a collective term that describes malignant tumors of the oral cavity, pharynx, and larynx characterized by high incidence and mortality rates. Although most HNSCC originate from the mucosal surface of the upper aerodigestive tract, where they can be easily detected during a routine clinical examination. Often the definitive diagnosis is delayed because of the difficulty in differentiating from other similar lesions. Activation of proto-oncogenes and inactivation of tumor suppressor genes are the major molecular alterations involved in carcinogenesis. In addition, epigenetic changes can alter the expression of critical genes important in the development of a variety of cancers. The detection of aberrant gene promoter methylation as a tool for the detection of tumors or its use as prognostic marker have been described for many different cancers including HNSCC. The search for biomarkers has as its main aim the evaluation and measurement of the status of normal and pathological biological processes as well as pharmacological responses to certain treatments. The tracking of these biomarkers is an important part for the identification of individuals in the early stages of head and neck cancer for its diagnostic and prognostic relevance reflecting in high survival rates, better quality of life and less cost to the healthcare system. Therefore, assuming that cancer results from genetic and epigenetic changes, analyzes based on gene methylation profile in combination with the pathological diagnosis would be useful in predicting the behavior of these head and neck tumors.
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Affiliation(s)
- L M R B Arantes
- Department of Molecular Biology, São José do Rio Preto Medical School (FAMERP), São José do Rio Preto - SP, Brazil; Center for Research in Molecular Oncology, Barretos Cancer Hospital - Pio XII, Barretos - SP, Brazil
| | - A C de Carvalho
- Center for Research in Molecular Oncology, Barretos Cancer Hospital - Pio XII, Barretos - SP, Brazil
| | - M E Melendez
- Center for Research in Molecular Oncology, Barretos Cancer Hospital - Pio XII, Barretos - SP, Brazil
| | - A L Carvalho
- Center for Research in Molecular Oncology, Barretos Cancer Hospital - Pio XII, Barretos - SP, Brazil
| | - E M Goloni-Bertollo
- Department of Molecular Biology, São José do Rio Preto Medical School (FAMERP), São José do Rio Preto - SP, Brazil.
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Liau JY, Liao SL, Hsiao CH, Lin MC, Chang HC, Kuo KT. Hypermethylation of the CDKN2A gene promoter is a frequent epigenetic change in periocular sebaceous carcinoma and is associated with younger patient age. Hum Pathol 2013; 45:533-9. [PMID: 24440092 DOI: 10.1016/j.humpath.2013.10.019] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2013] [Revised: 10/14/2013] [Accepted: 10/16/2013] [Indexed: 12/21/2022]
Abstract
Periocular sebaceous carcinoma is an aggressive neoplasm with significant morbidity and mortality. Its pathogenesis is poorly understood. It is only rarely associated with Muir-Torre syndrome. Previous studies from Asian countries, have suggested that human papillomavirus (HPV) infection plays a role in the pathogenesis and overexpression of p16(INK4a), a surrogate marker of HPV infection, have also been reported. However, data from western countries seem contradictory. In order to clarify and explore the molecular and epigenetic basis of HPV, CDKN2A status and role of microsatellite instability in the development of periocular sebaceous carcinoma, 24 cases of periocular sebaceous carcinoma were analyzed for the expression of p16(INK4a) and mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) via immunohistochemistry. Nested polymerase chain reaction (PCR) and genechip HPV typing were used to detect HPV infection and decide its genotype when present. PCR amplification using a consensus primer pair was also performed to detect β-HPV. The methylation status of CDKN2A promoter region was studied by methylation-specific polymerase chain reaction. HPV-positivity was demonstrated in only one of our cases (HPV 16), while another case showed p16(INK4a) overexpression. All cases showed preserved expression of mismatch repair proteins. CDKN2A promoter hypermethylation was noted in nearly half of our cases (11/24) and was associated with younger patient age (P = .013). Our results showed that periocular sebaceous carcinoma is rarely associated with HPV and microsatellite instability. Higher frequency of CDKN2A promoter hypermethylation in younger patients implies a significant epigenetic role in tumor development in this age group.
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Affiliation(s)
- Jau-Yu Liau
- Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10002, Taiwan; Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 10002, Taiwan
| | - Shu-Lang Liao
- Department of Ophthalmology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10002, Taiwan
| | - Cheng-Hsiang Hsiao
- Department of Pathology, Cheng Hsin General Hospital, Taipei 11220, Taiwan
| | - Ming-Chieh Lin
- Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10002, Taiwan
| | - Hsiao-Ching Chang
- Department of Ophthalmology, Taipei Hospital, Department of Health, New Taipei City 24213, Taiwan
| | - Kuan-Ting Kuo
- Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10002, Taiwan.
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Beadle BM, William WN, McLemore MS, Sturgis EM, Williams MD. p16 expression in cutaneous squamous carcinomas with neck metastases: a potential pitfall in identifying unknown primaries of the head and neck. Head Neck 2012; 35:1527-33. [PMID: 23108906 DOI: 10.1002/hed.23188] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/12/2012] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Human papillomavirus (HPV) positivity (+) has been used to identify oropharyngeal squamous carcinomas (SCCs) presenting as unknown primaries in the neck. p16 overexpression correlates with HPV+ in the oropharynx; however, the use of p16 alone as a surrogate marker of oropharyngeal HPV+ tumors has not been validated. METHODS We immunohistochemically analyzed p16 expression in surgically resected aggressive cutaneous head and neck SCC primaries and their nodal metastases from 24 patients to determine the potential overlap of p16 expression outside of the oropharynx. RESULTS Five of 24 primary tumors (20.8%) and 3 lymph node metastases (12.5%) in levels II, III, and V, and the periparotid region diffusely expressed p16. HPV (high-risk types by in situ hybridization) was negative. CONCLUSIONS p16 expression is relatively common in lymph node-positive cutaneous head and neck SCCs; thus, p16 expression as an independent biomarker and mechanism to determine the oropharyngeal source of an unknown primary is not advised.
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Affiliation(s)
- Beth M Beadle
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Yang CH, Huang CC, Ko MT, Wei YC, Hwang CF. Human papillomavirus infection and papillary squamous cell carcinoma in the head and neck region. Tumour Biol 2012; 34:301-7. [PMID: 23065573 DOI: 10.1007/s13277-012-0551-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 10/02/2012] [Indexed: 11/24/2022] Open
Abstract
Papillary squamous cell carcinoma (PSCC) is a rare variant of SCC in the head and neck region. The role of human papillomavirus (HPV) infection in PSCC is still unclear. We retrospectively reviewed 11 PSCCs in our institute over a 21-year period and compared the HPV status of PSCCs with 26 squamous cell papillomas (SCPs). Polymerase chain reaction (PCR) amplification to detect HPV DNA and in situ hybridization (ISH) were performed to analyze the relationship between the papillary lesions and HPV infection. Immunohistochemical (IHC) staining for p16 protein expression was used to analyze the PSCC specimens. Nine of 11 (82 %), eight of 11 (73 %), and eight of 11 (73 %) PSCC samples were found to be HPV positive by PCR, ISH, and IHC staining for p16 protein expression, respectively. PSCC had a significantly higher rate of HPV infection than SCP by PCR (p = 0.002) and ISH (p = 0.001) analysis. This study presents different HPV status in two papillary neoplasms and may help to clarify the unique morphological and biological characteristics of head and neck PSCC.
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Affiliation(s)
- Chao-Hui Yang
- Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China
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Vieira RAMAR, Minicucci EM, Marques MEA, Marques SA. Actinic cheilitis and squamous cell carcinoma of the lip: clinical, histopathological and immunogenetic aspects. An Bras Dermatol 2012; 87:105-14. [DOI: 10.1590/s0365-05962012000100013] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2010] [Accepted: 02/23/2011] [Indexed: 11/22/2022] Open
Abstract
Actinic cheilitis is the main precancerous lesion of the lip. Squamous cell carcinoma of the lip is reported together with oral carcinomas in the Brazilian official statistics. Overall, they account for 40% of the head and neck carcinomas. In general, physicians and dentists know little about what causes oral tumor development and progression. Tumor suppressor genes and cell proliferation regulatory proteins play a role in the progression of actinic cheilitis to squamous cell carcinoma and in its biological behavior. Knowledge on prognostic and diagnostic markers has a positive impact on the follow-up of these patients.
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Dasgupta S, Dash R, Das SK, Sarkar D, Fisher PB. Emerging strategies for the early detection and prevention of head and neck squamous cell cancer. J Cell Physiol 2012; 227:467-73. [PMID: 21465466 DOI: 10.1002/jcp.22767] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Despite significant improvements in therapeutic protocols, head and neck squamous cell carcinoma (HNSCC) remains a major health problem worldwide. The 5-year post-therapeutic survival rate is among the lowest of the major cancers with loco-regional relapse being the main cause of death. Moreover, in most instances, the quality of life of the afflicted patient is severely compromised. The poor prognosis for HNSCC is primarily due to disease detection at advanced stages. Accordingly, development of early detection and preventive strategies are essential. Recent advances in our understanding of the molecular biology and etiology of HNSCC should facilitate development of improved intervention and therapeutic approaches. The present review discusses the potential role of such factors for developing preventive and early diagnostic strategies for HNSCC management.
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Affiliation(s)
- Santanu Dasgupta
- Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
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Lee EH, Hwang DS, Shin SH, Kim UK, Chung IK, Kim YD. Impact of methylation of the p16 INK4agene on the prognosis ofhead and neck squamous cell carcinoma patients. J Korean Assoc Oral Maxillofac Surg 2012. [DOI: 10.5125/jkaoms.2012.38.2.101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Affiliation(s)
- Eui-Hoon Lee
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Dae-Seok Hwang
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Sang-Hun Shin
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Uk-Kyu Kim
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea
| | - In-Kyo Chung
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea
| | - Yong-Deok Kim
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, Yangsan, Korea
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Demokan S, Chuang A, Suoğlu Y, Ulusan M, Yalnız Z, Califano JA, Dalay N. Promoter methylation and loss of p16(INK4a) gene expression in head and neck cancer. Head Neck 2011; 34:1470-5. [PMID: 22106032 DOI: 10.1002/hed.21949] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Revised: 07/25/2011] [Accepted: 09/05/2011] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Silencing of tumor suppressor genes plays a vital role in head and neck carcinogenesis. In this study we aimed to evaluate aberrant p16(INK4a) gene promoter methylation in patients with head and neck cancer. METHODS Methylation of the gene was investigated by bisulfite modification/methylation-specific polymerase chain reaction and gene expression levels were analyzed by quantitative reverse transcription-polymerase chain reaction in tumors and matched normal tissue samples from Turkish patients with head and neck cancer. RESULTS The promoter region of the p16(INK4a) gene was methylated in 67.5% and 28.6% of the primary tumors and the corresponding normal tissue, respectively. This difference was highly significant. In concordance, p16(INK4a) gene expression was downregulated in 67.5% of the tumor samples. Methylation and the absence of expression in the tumors were observed in 48% of the patients. CONCLUSIONS Our data indicate that methylation of the p16(INK4a) gene is a frequent event in primary head and neck cancer and that it plays a major role in the silencing of p16(INK4a) gene expression during tumor development.
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Affiliation(s)
- Semra Demokan
- Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul, Turkey
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Shiga K, Ogawa T, Katagiri K, Yoshida F, Tateda M, Matsuura K, Kobayashi T. Differences between oral cancer and cancers of the pharynx and larynx on a molecular level. Oncol Lett 2011; 3:238-243. [PMID: 22740888 DOI: 10.3892/ol.2011.451] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Accepted: 10/11/2011] [Indexed: 11/06/2022] Open
Abstract
In order to elucidate differences between oral cancers and cancers of the pharynx and larynx, we investigated the genetic and epigenetic changes in these tumors using molecular biology methods. Methylation of the promoter region of the p16 tumor suppressor gene was examined using methylation-specific polymerase chain reaction in specimens from 47 oral, 39 pharyngeal and 35 laryngeal squamous cell carcinomas. These specimens were also characterized for allelic loss of certain areas of the genome, i.e., 3p22, 9p21 and 17p13 (TP53). The frequency of methylation of the promoter region of the p16 gene in tongue cancers (35.3%) was significantly higher than in pharyngeal (12.8%) and laryngeal cancers (11.4%) (p=0.046 and p=0.039, respectively). The frequency of methylation in tumors of female patients (47.1%) was significantly higher compared to tumors of male patients (15.4%) (p=0.0067). In contrast, the frequency of the loss of heterozygosity (LOH) at 3p21 in pharyngeal cancers (66.7%) was significantly higher than in oral cancers (20.0%) (p=0.0006). The frequencies of LOH at 17p13 in pharyngeal (71.0%) and laryngeal cancers (73.1%) were also significantly higher than in oral cancers (36.1%) (p=0.009 and p=0.009, respectively). Our results indicate that there are marked differences in the frequencies of the hypermethylation of genes and allelic loss between oral cancers and cancer of the pharynx and larynx. Although all of these tumors were diagnosed as squamous cell carcinomas, the process of carcinogenesis may be different in tumors located in various parts of the head and neck. Loss of function of tumor suppressor genes by allelic loss gives rise to tumors in the pharynx and larynx, while loss of function due to methylation of the promoter regions of those genes is related to carcinogenesis in the oral cavity.
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Affiliation(s)
- Kiyoto Shiga
- Department of Otolaryngology-Head and Neck Surgery, Iwate Medical University Hospital, Morioka, Iwate
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50
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Montebugnoli L, Venturi M, Gissi D, Leonardi E, Farnedi A, Foschini MP. Immunohistochemical expression of p16INK4A protein in oral lichen planus. ACTA ACUST UNITED AC 2011; 112:222-7. [DOI: 10.1016/j.tripleo.2011.02.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Revised: 02/15/2011] [Accepted: 02/15/2011] [Indexed: 11/25/2022]
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