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REVIEW ARTICLE
Year : 2009  |  Volume : 27  |  Issue : 1  |  Page : 2-5
 

The genomics of oral cancer and wound healing


Department of Preventive and Community Dentistry, Teerthankar Mahaveer Dental College and Research Center, Delhi Road, Moradbad, Uttar Pradesh, India

Correspondence Address:
Y B Aswini
Department of Preventive and Community Dentistry, Teerthankar Mahaveer Dental College and Research Center, Delhi Road, Moradbad, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-4388.50808

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   Abstract 

Oral cancer is the most common malignancy in India, where it is epidemiologically linked to the chewing of betel quid and other carcinogens. But various point mutations were detectable in the p53 and p15 genes. Hence, this review was conducted with the aim to find out genetic risks as well as markers for oral cancers and wound healing. Tobacco-related cancers are associated with polymorphisms of the CYP1A1 and GSTM1 genes in terms of genotype frequencies and cigarette smoking dose. Expression of E6/E7 were also found in tumors, most of which were derived from the oropharynx. Presence of homozygous arginine at codon 72 renders p53 about seven times more susceptible to E6-mediated proteolytic degradation. Erythropoietin, vascular permeability factor (VPF, also known as vascular endothelial growth factor or VEGF), and PDGF has been implicated as one of the principal mitogens involved in cutaneous wound healing. Activation of NF-kB is associated with enhanced cell survival. Human papilloma virus status is a significantly favorable prognostic factor in tonsilar cancer and may be used as a marker in order to optimize the treatment of patients with this type of cancer.


Keywords: Genetics, genetic screening, gene therapy, oral cancer, wound healing


How to cite this article:
Aswini Y B. The genomics of oral cancer and wound healing. J Indian Soc Pedod Prev Dent 2009;27:2-5

How to cite this URL:
Aswini Y B. The genomics of oral cancer and wound healing. J Indian Soc Pedod Prev Dent [serial online] 2009 [cited 2019 Nov 19];27:2-5. Available from: http://www.jisppd.com/text.asp?2009/27/1/2/50808



   Introduction Top


Head and neck squamous cell cancer (HNSCC) is the sixth most common cancer worldwide and has a severe impact on quality of life for patients and survivors. Oral squamous cell cancer (OSCC) incidence accounts for up to 40% of all malignancies in India and South East Asia. [1] Therefore, early diagnosis of high risk premalignant lesions and early cancers are high priorities for reducing the burden of HNSCC. In contrast to the current perception of HNSCC as a single progression mechanism, data support the idea that at least two progression routes to malignancy exist, with different prognosis. This new information on the mechanism of oral cancer development may lead to new ways of classifying this tumor type in relation to prognosis. A serious clinical problem is that, by current methods, it is impossible to identify in advance the 2-5% of the more common leukoplakias that will progress to cancer. Hence, this review was conducted with the aim of identifying the genetic risk as well as markers for oral cancer as well as wound healing. A thorough literature search yielded 56 articles, out of which relevant 38 articles were considered.


   Genomics of oral cancer and wound healing Top


Gene expression profiling has tried to identify different types of oral cancer and to investigate their relationships to premalignancies and the implications for prognosis. Firstly, understanding the molecular mechanisms may help to understand why cancer progresses, and secondly, identifying specific biological points appropriate for prevention strategies. One of the characteristics of normal cells is their limited proliferative potential, that is, they permanently cease proliferating ('senesce') after about 50 population doublings. During normal cell proliferation the ends of chromosomes (telomeres) become progressively shortened due to a phenomenon known as the 'end replication problem'. Senescence is thought to be triggered by signals generated by one or more telomeres reaching a critical length. About 40% of primary oral cancers (SCCs) and about 60% of dysplasias are mortal and undergo senescence. Mortal and immortal SCCs also differ in the expression of p53 and Rb/E2F target genes, including the novel p53 target, DRAM [Table 1]. [2]

The presence of specific alcohol dehydrogenase gene polymorphisms has been determined to confer differential susceptibility to the alcohol risk in certain populations. Genetic polymorphisms of several xenobiotic metabolizing agents, including the cytochrome P4501A1 , glucathione S transferase genes ( GSTMI ), and glucosyltransferase 1A7 ( UGT1A7 ) genes have increased risk for tobacco-related habits. [3]

In the cases, very high levels of expression of certain genes, p15 , the p65 subunit of the transcription factor (NF-kappa B), and I kappa B kinase, may lead to malignancy. [4] Lack of tumor suppressor gene PTEN may be an important prognostic factor of the SCC of tongue, expression of hepatocyte growth factor oncogene is involved in invasive metastatic change of HNSSCs. High expression of epithelial growth factor (EGFR) and the proactive cell nuclear antigen (PCNA) have been related with short patient survival and are thus of poor prognosis. Cyclin D 1 (CCND1) regulatory factors modulate the critical cell cycle control. CCND1 is overproduced, in a significant proportion of HNSSC with aggressiveness, early recurrence, and prognosis. Overexpression of CCND1 has been related to radiosensitivity and may be a prognostic factor of the effectiveness of radiation therapy on HNSSC. Antisense CCND1 may be useful, particularly in combination therapy, for instance with cisplatin, in treatment of HNSSC. [5],[6],[7]

An association between the presence of human papilloma virus (HPV) and the development of HNSSC has been established recently. [8],[9],[10],[11] A critical molecular parameter supporting a causal role of HPV-16 in HNSCC is the expression of the E6 and E7 oncogenes coupled with inactivation of pRB and p53 . Indeed, it has been shown that pRB protein levels are downregulated in HPV-16-positive HNSCC, a clear indication of E7 activity. [12],[13] Concerning E6 and p53 , the HPV-16-positive tumors could be classified into two groups. The tumors exhibited E6 gene expression and lacked p53 mutations or, alternatively, they lacked E6 expression and carried p53 mutations. [14] Infection with oncogenic HPV types and the other major risk factors for HNSCC, tobacco and alcohol, may represent alternative pathways in the development of these cancers. [15] The association of HNSCC with clinically significant morbidity and disfiguration makes the early detection of the diseases and biomarkers to identify individuals at high risk of great importance. One of the conclusions from a recent National Cancer Institute (NCI) workshop convened to assess viruses associated with human cancers [16] was that future HPV research needs to focus on developing a sensitive, validated laboratory test to detect HPV in oral exfoliated cells that would reflect HPV high risk types in head and neck tumors [Table 2]. HPVs are small oncogenic viruses, which are implicated in epithelial carcinogenesis, and p53 is a tumor suppressor gene with a central role in the prevention of genomic injury. HPV infection and activation of the H-ras gene is seen in oral verrucous carcinomas. These results continue to confirm the multihit hypothesis of tumorigenesis and suggest that in some cases of oral cancer at least two of these events are H-ras gene mutation and HPV infection. [17] Betel quid probably causes additional mutagenic steps in the carcinogenic process. [18] The E6 oncoproteins of these high risk HPVs are known to bind and induce degradation of p53 tumor suppressor protein through the ubiquitin pathways. This degradation is controlled by a common polymorphism of the p53 gene encoding either a proline or an arginine at its codon 72 in exon 4. [19] A polymorphisms of genes involved in metabolism of various endogenous and exogenous carcinogens are relatively common in most populations. [20] P450 cytochromes (CYP) are enzymes, which catalyze the insertion of one atom of molecular oxygen into a substrate. This is a typical reaction of activation (phase I), which converts indirect carcinogens into active electrophiles capable of interacting with the biological macromolecules DNA, RNA, and proteins. CYPs are coded by genes of the CYP super family. [21] Glutathione S-transferases are one of the major groups of detoxifying enzymes. NFjB controls the expression of a number of growth-promoting cytokines and the DNA-binding activity of NFjB is induced during the G0-G1 transition. NFjB also activates the expression of genes important for invasion and metastasis, [22] IjBa expression in tumor cell decreases the frequency of metastases. [5] Mutations in the IjBa gene have been detected in Hodgkin's lymphoma and are suggested to render NFjB constitutively active in Hodgkin's cells, consistent with a role for IjB as a tumor suppressor. [23] Insights into mechanisms by which nutritional factors affect the process of carcinogenesis are provided by knowledge of the targeted gene function and enzyme activity. Increased knowledge in this area will allow a more refined approach to reducing risk for cancer, with diet interventions targeted toward individuals and subgroups that are genetically susceptible and responsive to the effects of nutritional factors. [24]

Subpopulations exist who have increased genomic instability. These individuals are at an increased risk for the accumulation of DNA mutations and the development of head and neck cancer and multiple aberrations of chromosome 3p have been detected in oral premalignant lesions. [25] individuals with specific polymorphisms in the CYP1A1, GSTM1 genes, and zinc finger protein 217 have a genetically high risk of OSCC suggesting that an individual difference in the susceptibility to chemical carcinogens is one of the most important considerations in the risk assessment of oral cancers. [6]

The wound-healing process involves a complex interplay of cells, mediators, growth factors, and cytokines. [26] The cascade of events begins with clotting and recruitment of inflammatory cells and then proceeds to a highly proliferative state. During this proliferative phase, fibroblasts are involved in synthesis and remodeling of the collagen matrix, keratinocytes spread across the wound to form a new epithelial layer, and angiogenesis occurs. This latter step is crucial in the healing process. [27] During neovascularization, endothelial cells change their genetic program and express an angiogenic phenotype that includes the production of proteases, cell migration, and proliferation, followed by dedifferentiation, thus resulting in the formation of new blood vessels. [28] The formation of new blood vessels provides a route for oxygen and nutrient delivery, as well as a conduit for components of the inflammatory response. Healing is concomitant with an increasing release of angiogenic growth factors from macrophages and keratinocytes, such as vascular endothelial growth factor (VEGF), fibroblast growth factor and platelet-derived growth factor, and its impairment leads to a delay in skin repair. [29],[30] EPO, dose-dependently inhibited granulation tissue formation. RHuEPO gene is able to improve wound healing by stimulating granulation tissue formation neovascularization and dermal regeneration. This might be of particular relevance in the clinical situation of disturbed and delayed wound repair. [31]

Both Smad3 and its closely related homologue, Smad2, are intracellular mediators of TGF-β function, acting as nuclear transcriptional activators. [32] Smad2 and Smad3 mediate intracellular signalling from TGF-βs 1, 2, 3, and activin, each of which has been implicated as an important factor in the cellular proliferation, differentiation, and migration pivotal to cutaneous wound healing. Disruption of the Smad3 pathway in vivo , coupled with exogenous TGF signaling through intact alternate pathways, may be of therapeutic benefit in accelerating all aspects of impaired wound healing. [33]

Gene identification is only the first step toward understanding of human disease at the most fundamental level. Cancer genetic counselors are involved with individuals with cancer or with a family history of cancer. Gene therapy can be done using these genetic targets for oral cancers as well as bone repair and wound healing. Gene therapy strategies for head and neck carcinomas are suicide gene therapy or genetic prodrug activation therapy, Gene replacement therapy, adenovirus E1 region gene therapy, and immunological gene therapy; tissue engineering of soft tissues and bone is a not a dream because of the tremendous achievements in genetics, proteomics, and molecular biology. [34],[35],[36],[37],[38] We can hope a new future for patients of oral cancer in the near future.

 
   References Top

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8.Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L, et al. Evidence for a causal association between HPV and a subset of head and neck cancers. J Natl Cancer Inst 2000;92:709-20.  Back to cited text no. 8    
9.Steenbergen RD, Hermsen MA, Walboomers JM, Joenje H, Arwert F, Meijer CJ, et al. Integrated human papillomavirus type 16 and loss of heterozygosity at 11q22 and 18q21 in an oral carcinoma and its derivative cell line. Cancer Res 1995;55:5465-71.  Back to cited text no. 9    
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11.Franceschi S, Munoz N, Snijders PJ. How strong and how wide is the link between HPV and oropharyngial cancer? Lancet 2000;356:871-2.  Back to cited text no. 11    
12.Andl T, Kahn T, Pfuhl A, Nicola T, Erber R, Conradt C, et al. Etiological involvment of oncogenic HPV in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control. Cancer Res 1998;58:5-13.  Back to cited text no. 12    
13.Wiest T, Schwarz E, Enders C, Flechtenmacher C, Bosch FX. Involvement of intact HPV 16 E6/E7 gene expression in head and neck cancers with unaltered p53 status and perturbed pRb cell cycle control. Oncogene 2002;21:1510-7.  Back to cited text no. 13    
14.van Houten VM, Snijders PJ, van den Brekel MW, Kummer JA, Meijer CJ, van Leeuwen B, et al. Biological evidence that human papillomaviruses are etiologically involved in a subgroup of head and neck squamous cell carcinomas. Int J Cancer 2001;93:232-5.  Back to cited text no. 14    
15.Smith EM, Hoffman HT, Summersgill KS, Kirchner HL, Turek LP, Haugen TH. Human papillomavirus and risk of oral cancer. Laryngoscope 1998;108:1098-103.  Back to cited text no. 15    
16.Wong M, Pagano JS, Schiller JT, Tevethia SS, Raab-Traub N, Gruber J. New associations of human papillomavirus, Simian virus 40, and Epstein-Barr virus with human cancer. J Natl Cancer Inst 2002;94:1832-6.  Back to cited text no. 16    
17.Anderson JA, Irish JC, McCachlin CM, Ngan BY. H-ras ongogene mutation and human papillomavirus infection in oral carcinomas. Arch Otolaryngol Head Neck Surg 1994;120:755-60.  Back to cited text no. 17    
18.Balaram P, Nalinakumari KR, Abraham E, Balan A, Hareendran NK, Bernard HU, et al. Human papillomaviruses in 91 oral cancers from Indian betel quid chewers-high prevalence and multiplicity of infections. Int J Cancer 1995;61:450-4.  Back to cited text no. 18    
19.Katiyar S, Thelma BK, Murthy NS, Hedau S, Jain N, Gopalkrishna V, et al. Polymorphism of the p53 codon 72 Arg/Pro and the risk of HPV type 16/18- associated cervical and oral cancer in India. Mol Cell Biochem 2003;252:117-22.  Back to cited text no. 19    
20.Miller CS, Johnstone BM. Human papillomavirus as a risk factor for oral squamous cell carcinoma: A meta analysis, 1982-1997. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91:622-35.  Back to cited text no. 20    
21.Misra C, Majumder M, Bajaj S, Ghosh S, Roy B, Roychoudhury S. Polymorphisms at p53, p73, and MDM2 loci modulate the risk of tobacco associated leukoplakia and oral cancer. Mol Carcinog 2009 Feb 9.  Back to cited text no. 21    
22.Newton TR, Patel NM, Bhatt-Nakshatri P, Stauss CR, Goulet RJ Jr, Nakshatri H. Negative regulation of transactivation function but not DNA binding of NF-jB and AP-1 by IjBb1 in breast cancer cells. J Biol Chem 1999;274:18827-35.  Back to cited text no. 22    
23.Cabannes E, Khan G, Aillet F, Jarrett RF, Hay RT. Mutations in the IjBa gene in Hodgkin′s disease suggest a tumour suppressor role for IjBa. Oncogene 1999;18:3063-70.  Back to cited text no. 23    
24.Nair S, Pillai MR. Human papillomavirus and disease mechanisms: Relevance to oral and cervical cancers. Oral Dis 2005;11:350-9.  Back to cited text no. 24    
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31.Galeano M, Altavilla D, Cucinotta D, Russo GT, Calò M, Bitto A, et al. Recombinant human erythropoietin stimulates angiogenesis and wound healing in the genetically diabetic mouse. Diabetes 2004;53:2509-17.  Back to cited text no. 31    
32.Roberts AB. Transforming growth factor-b: Activity and efficacy in animal models of wound healing. Wound Repair Regen 1995;3:408-18.   Back to cited text no. 32    
33.Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JJ, Mizel DE, et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Cell Biol 1999;1: 26.  Back to cited text no. 33    
34.Gotoh A, Kao C, Ko SC, Hamada K, Liu TJ, Chung LW. Cytotoxic effects of recombinant adenovirus P 53 and cycle regulators genes (p21 and p16) in human prostate cancer. J Urol 1997;158:636-41.  Back to cited text no. 34    
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    Tables

  [Table 1], [Table 2]


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