|Year : 2021 | Volume
| Issue : 2 | Page : 86-92
Oral cancer and genomics
Preeti Nair1, Priyanka Deepak Deshmukh1, Akhil M Trivedi1, Joshua Shaji Thomas2
1 Department of Oral Medicine and Radiology, People's College of Dental Sciences and Research Centre, Bhopal, Madhya Pradesh, India
2 Graduate, BDS, Healing Touch Dental Clinic, Indrapuri, Bhopal, Madhya Pradesh, India
|Date of Submission||06-May-2021|
|Date of Decision||21-Jun-2021|
|Date of Acceptance||03-Jul-2021|
|Date of Web Publication||17-Jan-2022|
Dr. Priyanka Deepak Deshmukh
Department of Oral Medicine and Radiology, People's College of Dental Sciences and Research Centre, Bhopal - 462 037, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Oral cancer is a leading cause of death, especially in developing countries. Head-and-neck squamous cell carcinoma is the sixth most common cancer worldwide. It accounts for 1.9% death annually due to delay in diagnosis and treatment strategies. Oral carcinogenesis is a multistep process. Recent advances in the understanding of the molecular control of these various pathways will facilitate more accurate diagnosis and assessment of prognosis and can pave the way for more novel approaches to treatment and prevention. This review highlights the major genes involved in oral carcinogenesis and emphasizes on the implementation of genomics, which can be the new paradigm for drug development and targeted therapeutics.
Keywords: Genes, genomics, oncogenes, tumor suppressor protein p53
|How to cite this article:|
Nair P, Deshmukh PD, Trivedi AM, Thomas JS. Oral cancer and genomics. J Int Clin Dent Res Organ 2021;13:86-92
| Introduction|| |
Biological sciences concerned with when, where, and how genes are expressed and how is differential gene regulation associated with specific patterns throughout the human life span has become one of the most fascinating areas for research studies. Scientific advances and emphasis on evidence-based approach in medical and dental health practices have improved the survival rate and quality of life of many individuals. With diseases being identified in its initial stages and a few diagnosed even before the onset, the field of genetics has become an applied science, from merely being an academic trail.
The answer to the quest in concern with the causation of the disease and various host responses lies in the genome of each organism. Human genome determines what diseases are on perspective and promises to improve the diagnosis so that effective tailored treatment can be provided to the individuals.,
Cancer is considered to be the disease of genome. The Human Genome Project has helped to identify regions of the genome harboring genes altered in cancer, mutations in specific genes, and identify genes with an altered expression profile in cancer cells. The technological advances coupled with the draft human genome sequence have not just increased the pace of cancer research but have provided a completely new view of cancer cells, allowing us to see the whole cell at once, rather than bits of the cellular machinery in isolation.
In the recent years, cancer research studies have focused on understanding the genetic alteration, discrete mutations, and perturbation of associated cellular and molecular pathways that lead to initiation and progression of carcinogenesis. Detection of genetic changes at the level of DNA and learning the expression of genes that govern signals of cell cycle is fundamental to these research studies. The multistep event of carcinogenesis proceeds in a sequential order requiring both activation of transforming genes and inactivation of recessive tumor suppressor genes., Furthermore, the recognition of Mendelian inheritance in families with cancer and the identification of genetic markers in such families with cancer have opened new avenues for investigation, through so-called predisposing genes.
Oral cancer causes significant morbidity and mortality, especially in low socioeconomic status groups and has been recognized as the cause of two-thirds of all cancers related deaths in the developing world., It has been estimated that from 3 to 6 somatic mutations are needed to transform a normal cell into its malignant counterpart., As the cell accumulates these alterations or mutations, it becomes functionally independent from the surrounding cells and is subverted to tumor cells. These tumor cells have the ability to proliferate, stimulate neovascularization, and grow by invading locally or metastasizing to distant sites.,, The molecular studies on oral cancer and precancer lesions serve as the basis to augment not only clinical assessment and classification of oral lesions but also predict their malignant potential more accurately.
This review highlights major genes involved in oral carcinogenesis and emphasizes on the implementation of genomics which can be the new paradigm for drug development and targeted therapeutics.
| Cytogenetic Implications in Oral Squamous Cell Carcinoma|| |
Genetic alterations occurring during carcinogenesis include point mutations, amplifications, rearrangements, and deletions. Multiple sequential genetic events lead to cancer, with 6–10 genetic events believed to result in oral carcinogenesis.
Early studies defining a progression model for cancers of the upper aerodigestive tract implicated loss of heterozygosity (LOH) as a mechanism by which genetic loci containing tumor suppressor genes are eliminated. LOH is reported at 9p21–p22 chromosome containing gene p16INK4a/p14ARF/CDKN2A in 72% of tumors (preinvasive and invasive state) and is found to be the most common early genetic event. This region of 9p21 encodes the tumor suppressors p16 which is frequently inactivated by promoter hypermethylation (Reed et al., 1996).
Loss of the 3p region is an early cytogenetic change in oral carcinogenesis. Benign hyperplastic lesions and precancerous lesions show loss of 9p21 or 3p in 30% of cases.
LOH of chromosome region 17p and mutation of the p53 gene are genetic alterations that occur in the later stage of progression from dysplasia to invasive squamous carcinoma. Alterations of p53, including mutation or deletion, are associated with increased genomic instability in oral dysplasia and may accelerate the rate of genetic alterations in oral carcinogenesis. Other than LOH, point mutation is also seen in p53. Amplifications and rearrangements are seen to affect the genes involved in excitatory pathways, whereas rearrangement can also inactivate inhibitory pathway genes.
Amplification of 11q13 has been observed in around one-third of head-and-neck cancers. This region contains the proto-oncogene cyclin D1/parathyroid adenomatosis 1 (PRAD1)/CCD1, whose function is to activate pRb by phosphorylation, facilitating progression of the cell cycle from the G1 (growth) to the S (synthesis) phase. As a result of amplification of this region, cyclin D1 is overexpressed in oral cancers. According to study conducted by Mineta et al., cyclin D1 overexpression has been associated with more aggressive tumor behavior and a worse prognosis than tumors that do not overexpress cyclin D1.
Other important cell cycle checkpoints that contribute to increased cell proliferation include cyclin B, E, and A. Overexpression of cyclin A and B has been reported in oral carcinomas and with cyclin A overexpression being associated with adverse prognosis in oral precancer and cancer.
Common cytogenetic alterations occurring in head-and-neck carcinomas have been listed [Table 1].
| Oncogenes and Proto-oncogenes|| |
The key regulatory factors of biological process in a normal cell are proto-oncogenes. Proto-oncogenes encode proteins that mediate signals pathways for cell growth and cell survival. When the proto-oncogene mutates to become an oncogene, it can promote uncontrolled cell proliferation, leading to tumorigenesis.
Some of the common mechanisms of oncogene activation include mutation, chromosomal translocation, gene amplification, and retroviral insertion.,
Proto-oncogenes are broadly categorized into various functional groups [Table 2].
Epidermal growth factor receptor (EGFR), the biological receptor of epidermal growth factor (EGF), is frequently overexpressed in oral cancer and influences cell division, migration, adhesion, differentiation, and apoptosis through the tyrosine-kinase pathway. Elevated expression of EGF is a predictor of recurrence. Expression of its transmembrane receptor (EGFR) has been detected in 40%–80% of oral squamous cell carcinoma (OSCC) cases and has been proposed to have prognostic value.
EGFR/c-erb 1 and members of gene families ras, c-myc, int-2/fibroblast growth factor-3, hst-1/heparin-binding secretory transforming factor 1, PRAD1, and B-cell leukemia/lymphoma 1 are implicated in oral carcinogenesis. By overriding the G/M, G/S, and M checkpoints of the cell cycle, these oncogenes promote aberrant cell proliferations.,
Early event in carcinogenesis witnesses aberrant expression of transforming growth factor-α (TGF-α). It is first observed in hyperplastic epithelium and then in OSCC, in the infiltrate of inflammatory cells around the infiltrating epithelium, especially eosinophils. TGF-α stimulates cell proliferation by autocrine and paracrine binding to EGFR. It is also believed to stimulate angiogenesis.
Members of the ras oncogene family are overexpressed in oral cancer. Loss of control of N-ras may be an early step in oral carcinogenesis. Oncogene ras mutations are infrequent in Western patients and detected in fewer than 5% of oral cancers. In contrast, 55% of lip cancers have H-ras mutation, which is also present in 35% of oral cancers in Asian population.,
Transcription factor C-Myc induces cell proliferation and, in combination with p53, abrogates apoptosis. Nuclear protein pRb of the pRb gene interacts with the c-myc gene, hindering its transcription and thereby inhibiting cell proliferation. This gene is frequently overexpressed in OSCC as a result of gene amplification.
| Transcription Pathway and Tumor Suppressor Genes|| |
The process of copying a segment of DNA into ribonucleic acid (RNA) is called transcription. The stretch of DNA that can be transcribed into RNA molecule that encodes the protein is termed messenger RNA (mRNA). The other stretches of DNA are transcribed into what is called as noncoding RNA (ncRNA). Genetic changes in oral cancer cells could be dominant or recessive. The former involves changes in proto-oncogenes and tumor suppressor genes resulting in gain of function; the latter changes are noted in growth inhibitory pathway and cause loss of function. A cascade of intracellular biochemical steps, like regulation of protein phosphorylation, is activated by ligand receptor binding. In oral tumors, the mechanisms that may activate EGFR genes are deletion in the C-terminus of the receptor, overexpression of EGFR gene, and mutation in the N-terminal ligand binding domain. Among the intracellular signaling pathways, mutations of the ras genes may play a role in oral cancer.
Tumor suppressor genes are frequently inactivated by rearrangements in both copies of the gene. Among the most widely studied tumor, suppressor genes are rb and p53, which express pRb (retinoblastoma protein) and p53 protein, respectively. These proteins control the cell cycle and mutations in these proteins produce uncontrolled cell proliferation. The absence of pRb expression was observed in 66% of OSCCs and 64% of premalignant lesions. 90% of OSCCs and 83% of premalignant lesions showed altered expression of some protein of the pRb pathway.
p53 acts as transcription factor of cell inhibitors such as p21Waf1/Cip1/Sdi1 and prevents the cell from going beyond phase G1 of the cell cycle, permitting DNA repair. If this is not possible, p53 induces apoptosis of these cells. The p53 gene is inactivated in approximately half of HNC cases. Overexpression of protein p53 and gene mutation have also been detected in oral epithelial dysplasia and OSCC lesions. Both copies of a tumor-suppressor gene must be in an inactive state before a cancer cell can proliferate or survive further. LOH may be caused by intermediate deficiencies, deletions of chromosomes, or abnormal mitotic divisions and is thought to reflect the loss of one or more tumor-suppressor genes.
| Epigenetic Events|| |
The word epigenetics which literally means above the genome studies heritable changes caused by deactivation and activation of genes without changes in the DNA sequence of the organism. The DNA molecule can be modified by the addition or subtraction of methyl groups without a change in the base composition. Within a species, the whole DNA content in somatic cells remains the same but gene expression patterns have distinct differences among cell type that can be inherited. Epigenetic mechanisms can influence the gene activity at the transcriptional and posttranscriptional level or cause modification at the translational level. Hence, modifications of DNA, histones, and DNA-binding proteins, which are crucial in making changes to chromatin structure, are involved in epigenetics.
In OSCC RNA interference (RNAi), histone modifications and DNA hypermethylation are the major epigenetic mechanisms.
Hypermethylation is a well-characterized epigenetic modification and is implicated in the inactivation of many tumor suppressor genes. This results in changes in the amount and distribution of 5-methylcytosine (5mc) and is implicated in the development of disease. Spafford et al. studied and found abnormal methylation patterns of p16, methylguanine-DNA methyltransferase, and death-associated protein kinase genes in smears of patients suffering from head-and-neck cancer. Changes in the methylation patterns can modify the tumor behavior and can repress transcription.
Histone proteins serve as spools that wind DNA strands to package cellular DNA into nucleosomes.
The prominent histone modification alterations in OSCC and potentially malignant disease include H2A hyperphosphorylation, H3 hypo/hyperacetylation, H3 methylation reduction/increase, and H4 hypoacetylation. The key regulators of gene expression, genome stability, and defense against foreign genetic elements range from small to long ncRNAs.
Two types of small RNA molecules are involved with preventing mRNA from producing a protein; these include micro-RNA (miRNA) and small interfering RNA (siRNA). RNAi is a powerful physiological process, which protects cells from viruses and transposons. Double-stranded RNA (dsRNA) has better ability in gene silencing as compared to single-stranded RNA, and RNAi technology is based on target transcript expression of degradation by the dsRNA. The first phase in the interference mechanism involves hydrolysis of exogenous small dsRNA to siRNA by dicer endoribonuclease. Subsequently, siRNA binds to RNA-induced silencing complex.
miRNAs are small, nontranscribed RNA molecules, approximately 22 nucleotides in length, that contribute to a complex termed the RNA-silencing complex, which binds to specific sequences in mRNA strands and directs gene silencing. They exert a suppressive effect on posttranscriptional regulation of target genes by degradation or translational repression of mRNA. Levels of miRNA in saliva, serum, and plasma serve as potential tools in early diagnosis of oral cancer. Furthermore, their use as prognostic biomarkers or target for novel therapy in oral cancer and precancer is being explored. Ghosh et al. stated that miR-221, miR-155, miR-21, miR-191 were upregulated while miR-1, miR-205, miR-133a were downregulated in head-and-neck squamous cell carcinoma (SCC). A combination of mutation and epigenetic mechanisms is involved in the multistep process that leads to the emergence of a population of cells with a malignant phenotype.
| Therapeutic Potential Value|| |
Our improved understanding about the genomics of cancer and hallmark of OSCC has driven us toward targeted therapies and gene therapies. The advent of increasingly sophisticated molecular detection techniques and technologies has made identification of the involved genes easier.
Target therapies are intended to cause cancer cells lysis and death, decrease the blood supply to the tumor, and introduce genes into the cancer cells that cause death or restore normal cellular phenotype. The molecule which is absolutely specific to cancer cells and is involved in multiple pathways of carcinogenesis can be the focus of targeted therapies.
The known genes and proteins can act as markers for the diagnosis and prognosis of the disease and direct the treatment protocols. Furthermore, instead of relying on single genetic marker, a combination of different genetic markers and protein may offer more promising diagnostic and prognostic value.
Many early studies on the molecular basis of head-and-neck cancer have demonstrated an association between p53 abnormalities and poor outcome. Furthermore, the prognostic significance of p16 aberrations, EGFR, and cyclin D1 overexpression has shown to be associated with a worse prognosis in head-and-neck SCC. Many potential targets have been studied to predict the clinical outcome in OSCC. These are involved in growth regulation (EGFR), angiogenesis (vascular endothelial growth factor), apoptosis (p53), and inflammation (cyclo-oxygenase-2 pathway).
Gene therapy has shown remarkable efficacy with more sophisticated and personalized approach.
Gene therapy regime includes immunotherapy, oncolytic viral therapy, and gene transfer. It relies on the genetics of cancer by manipulating the genes using genes.
The current researches in this field are directed to create recombinant cancer vaccines which are meant to effectuate cure by modulating the immune system of the patient to recognize the cancer cells by presenting it with highly antigenic and immunostimulatory cellular debris.,
Much progress is evident in the field of oncolytic virotherapy where viruses genetically engineered and converted into oncocytic vectors to target and destroy cancer cells while remaining innocuous to the rest of the body. Different viruses have been used for this purpose, including vaccinia, adenovirus, and herpes simplex virus Type I.
Furthermore, the new treatment paradigm involving the introduction of a foreign gene into the cancer cell or surrounding tissue is gene transfer. Proposed prospects of gene transfer are suicide genes (genes that cause cellular death when expressed), antiangiogenesis genes, and cellular stasis genes.
These new treatment strategies seem promising yet their incorporation into the clinical practice is one of the major challenges on the horizon of cancer treatment.
| Conclusion|| |
Cancer which is a noncommunicable disease accounts for 9% of deaths in India. A combination of habits, environment, and malnutrition is thought to bring about changes at the cellular level, which lead to the cumulative risk of cancer progression. Remarkable progress has been made in the field of cellular and molecular studies of oral cancer. Technology has opened doors to increase our knowledge on cellular behavior, erratic pathways all of which involved genomics in a grand way. Tumorigenic genetic alterations are much clearer; however, we still have miles to go. Therapy prognosis and prevention of cancer are largely dependent on a comprehensive understanding. Early screening and advancements in detection methods using genomics could provide respite by reducing the morbidity and mortality in oral cancer.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Slavkin HC. Splice of life: Toward understanding genetic determinants of oral diseases. Adv Dent Res 1989;3:42-57.
Slavkin HC. The human genome, implications for oral health and diseases, and dental education. J Dent Educ 2001;65:463-79.
Anderson WF. Prospects for human gene therapy. Science 1984;226:401-9.
Stadler ME, Patel MR, Couch ME, Hayes DN. Molecular biology of head and neck cancer: Risks and pathways. Hematol Oncol Clin North Am 2008;22:1099-124, vii.
Sàndor GK, Carmichael RP, Coraza L, Clokie CM, Jordan RC. Genetic mutations in certain head and neck conditions of interest to the dentist. J Can Dent Assoc 2001;67:594.
Weber BL. Cancer genomics. Cancer Cell 2002;1:37-47.
Williams HK. Molecular pathogenesis of oral squamous carcinoma. Mol Pathol 2000;53:165-72.
Jurel S, Gupta D, Singh R, Singh M, Srivastava S. Genes and oral cancer. Indian J Hum Genet 2014;20:4.
] [Full text]
Bishop JM. Molecular themes in oncogenesis. Cell 1991;64:235-48.
Ankathil R, Mathew A, Joseph F. Is oral cancer susceptibility inherited? Eur J Cancer B Oral Oncol 1996;32B: 63-7.
Silverman S Jr, Gorsky M. Epidemiologic and demographic update in oral cancer: California and national data – 1973 to 1985. J Am Dent Assoc 1990;120:495-9.
Bagan J, Sarrion G, Jimenez Y. Oral cancer: Clinical features. Oral Oncol 2010;46:414-7.
Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet 1993;9:138-41.
Sidransky D. Molecular genetics of head and neck cancer. Curr Opin Oncol 1995;7:229-33.
Weiner T, Cance WG. Molecular mechanisms involved in tumorigenesis and their surgical implications. Am J Surg 1994;167:428-34.
Kuper H, Adami HO, Trichopoulos D. Infections as a major preventable cause of human cancer. J Intern Med 2000;248:171-83.
Mithani SK, Mydlarz WK, Grumbine FL, Smith IM, Califano JA. Molecular genetics of premalignant oral lesions. Oral Dis 2007;13:126-33.
Califano J, van der Riet P, Westra W, Nawroz H, Clayman G, Piantadosi S, et al.
Genetic progression model for head and neck cancer: Implications for field cancerization. Cancer Res 1996;56:2488-92.
Garnis C, Baldwin C, Zhang L, Rosin MP, Lam WL. Use of complete coverage array comparative genomic hybridization to define copy number alterations on chromosome 3p in oral squamous cell carcinomas. Cancer Res 2003;63:8582-5.
Kim MM and Califano JA: Molecular pathology of head-and neck cancer. Int J Cancer 2004;112:545-53.
Todd R, Donoff RB, Wong DT. The molecular biology of oral cancer: Toward a tumour progression model. J Oral Maxillofac Surg 1997;55:613-23.
Kotelnikov VM, Coon JS 4th
, Mundle S, Kelanic S, LaFollette S, Taylor S IV, et al.
Cyclin D1 expression in squamous cell carcinomas of the head and neck and in oral mucosa in relation to proliferation and apoptosis. Clin Cancer Res 1997;3:95-101.
Mineta H, Miura K, Takebayashi S, Ueda Y, Misawa K, Harada H, et al.
Cyclin D1 overexpression correlates with poor prognosis in patients with tongue squamous cell carcinoma. Oral Oncol 2000;36:194-8.
Monteiro LS, Diniz-Freitas M, Warnakulasuriya S, Garcia-Caballero T, Forteza-Vila J, Fraga M. Prognostic significance of cyclins A2, B1, D1, and E1 and CCND1
numerical aberrations in oral squamous cell carcinomas. Anal Cell Pathol (Amst) 2018;2018:7253510.
Kontomanolis EN, Koutras A, Syllaios A, Schizas D, Mastoraki A, Garmpis N, et al.
Role of oncogenes and tumor-suppressor genes in carcinogenesis: A review. Anticancer Res 2020;40:6009-15.
Klein G, Klein E. Evolution of tumours and the impact of molecular oncology. Nature 1985;315:190-5.
Haluska FG, Tsujimoto Y, Croce CM. Oncogene activation by chromosome translocation in human malignancy. Annu Rev Genet 1987;21:321-45.
Chang LC, Chou MY, Chow P, Matossian K, McBride J, Tao CA, et al.
Detection of transforming growth factor-alpha messenger RNA in normal and chemically transformed hamster oral epithelium by in situ
hybridization. Cancer Res 1989;49:6700-7.
Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 1993;53:3579-84.
Field JK. The role of oncogenes and tumour-suppressor genes in the aetiology of oral, head and neck squamous cell carcinoma. J R Soc Med 1995;88:35P-39P.
Choi S, Myers JN. Molecular pathogenesis of oral squamous cell carcinoma: Implications for therapy. J Dent Res 2008;87:14-32.
Todd R, Chou MY, Matossian K, Gallagher GT, Donoff RB, Wong DT. Cellular sources of transforming growth factor-alpha in human oral cancer. J Dent Res 1991;70:917-23.
Yarbrough WG, Shores C, Witsell DL, Weissler MC, Fidler ME, Gilmer TM. Ras mutations and expression in head and neck squamous cell carcinomas. Laryngoscope 1994;104:1337-47.
Saranth D, Chang SE, Bhoite LT. High frequency mutations in codons 12 and 61 of Ha-ras oncogene in chewing tobacco-related human oral carcinoma in India. Br J Cancer 1991;63:573-8.
Field JK. Oncogenes and tumour-suppressor genes in squamous cell carcinoma of the head and neck. Eur J Cancer B Oral Oncol 1992;28B: 67-76.
Schantz SP. Basic science advances in head and neck oncology: The past decade. Semin Surg Oncol 1995;11:272-9.
Wee P, Wang Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers (Basel). 2017;9:52. doi:10.3390/cancers9050052.
Pande P, Mathur M, Shukla NK, Ralhan R. pRb and p16 protein alterations in human oral tumorigenesis. Oral Oncol 1998;34:396-403.
Soni S, Kaur J, Kumar A, Chakravarti N, Mathur M, Bahadur S, et al.
Alterations of rb pathway components are frequent events in patients with oral epithelial dysplasia and predict clinical outcome in patients with squamous cell carcinoma. Oncology 2005;68:314-25.
Worsham MJ, Chen KM, Meduri V, Nygren AO, Errami A, Schouten JP, et al.
Epigenetic events of disease progression in head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2006;132:668-77.
Weinhold B. Epigenetics: The science of change. Environ Health Perspect 2006;114:A160-7. doi:10.1289/ehp.114-a160.
Moosavi A, Motevalizadeh Ardekani A. Role of epigenetics in biology and human diseases. Iran Biomed J 2016;20:246-58.
Hema KN, Smitha T, Sheethal HS, Mirnalini SA. Epigenetics in oral squamous cell carcinoma. J Oral Maxillofac Pathol 2017;21:252-9.
] [Full text]
Ehrlich M. DNA hypermethylation in disease: Mechanisms and clinical relevance. Epigenetics 2019;14:1141-63.
Spafford MF, Koch WM, Reed AL, Califano JA, Xu LH, Eisenberger CF, et al.
Detection of head and neck squamous cell carcinoma among exfoliated oral mucosal cells by microsatellite analysis. Clin Cancer Res 2001;7:607-12.
Yang H, Jin X, Dan H, Chen Q. Histone modifications in oral squamous cell carcinoma and oral potentially malignant disorders. Oral Dis 2020;26:719-32.
Holoch D, Moazed D. RNA-mediated epigenetic regulation of gene expression. Nat Rev Genet 2015;16:71-84.
Sobecka A, Barczak W, Suchorska WM. RNA interference in head and neck oncology. Oncol Lett 2016;12:3035-40.
Jansson MD, Lund AH. MicroRNA and cancer. Mol Oncol 2012;6:590-610.
Fang C, Li Y. Prospective applications of microRNAs in oral cancer. Oncol Lett 2019;18:3974-84.
Ghosh RD, Pattatheyil A, Roychoudhury S. Functional Landscape of dysregulated MicroRNAs in oral squamous cell carcinoma: Clinical implications. Front Oncol 2020;10:619.
You JS, Jones PA. Cancer genetics and epigenetics: Two sides of the same coin? Cancer Cell 2012;22:9-20.
Cross D, Burmester JK. Gene therapy for cancer treatment: Past, present and future. Clin Med Res 2006;4:218-27.
Nawrocki S, Wysocki PJ, Mackiewicz A. Genetically modified tumour vaccines: An obstacle race to break host tolerance to cancer. Expert Opin Biol Ther 2001;1:193-204.
Mullen JT, Tanabe KK. Viral oncolysis. Oncologist 2002;7:106-19.
Patil SD, Rhodes DG, Burgess DJ. DNA-based therapeutics and DNA delivery systems: A comprehensive review. AAPS J 2005;7:E61-77.
[Table 1], [Table 2]