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International Journal of Dentistry and Oral Health Volume 5 Issue 5, July 2019

International Journal of Dentistry and Oral Health

Review Article ISSN 2471-657X Oncogenic Viruses In Oral Neoplasia Dr. Divya Raj* Assistant Professor, Dental Division Regional Centre, Trivandrum, Kerala,

Abstract Neoplasia literally means “new growth.” During the past 30yrs it has become exceedingly apparent that several viruses play significant role in multistage development of human . Approximately 15-20% of are associated with viral infection. Oral squamous cell shows multiphasic and multifactorial etiopathogenesis. Most commonly implicated viruses in oral are Human Virus (HPV), Herpes group viruses, Adenoviruses and Hepatitis C virus.

Key words: Biofilm, Cleft, Palatal expander, Streptococcus

etiopathogenesis.[5] Common risk factors for oral cancer are Corresponding Author: Dr. Divya Raj and . It was found that there is a parallel reduction in the inci- Assistant Professor, Dental Division Regional Cancer Centre, Trivan- dence of oral cancer with lowering of tobacco and alcohol consump- drum, Kerala, India. tion. But increase in the incidence of carcinoma tonsil and base of Email: [email protected] which has least association with tobacco and alcohol shows [6] Citation: Dr. Divya Raj (2019), Oncogenic Viruses in Oral Neoplasia. role of other etiological agents in their development. Most common- Int J Dent & Oral Heal. 5:5, 68-74 ly implicated viruses in oral carcinogenesis are Human Papilloma Virus (HPV), Herpes group viruses, Adenoviruses and Hepatitis C virus.[7]Of Copyright: ©2019 Dr. Divya Raj. This is an openaccess article these HPVs and Herpes viruses are the “synergistic viruses” involved distributed under the terms of the Creative Commons Attribution in oral cancer. License, which permits unrestricted use, distribution, and reproduction Oral carcinogenesis in any medium, provided the original author and source are credited Oral carcinogenesis is a complex, multistep process in which genetic Received: May 18, 2019 events within signal transuduction pathways governing normal cellu- Accepted: May 28, 2019 lar physiology are quantitatively or qualitatively altered. Basic cellular functions include cell division, differentiation, and cell death -(Apop July 12, 2019 Published: tosis). The regulation of apoptosis and cell proliferation is controlled by , tumor suppressor genes, and growth factors. Random mutations in the genes, which control proliferation or apoptosis are Introduction responsible for cancer. Precise regulation of all this positive and neg- Neoplasia literally means “new growth.” Willis defined as ative signalling is essential to maintain normal cell growth, and distur- “an abnormal mass of tissue the growth of which exceeds and is un- bance of such regulation can lead to neoplasia. coordinated with that of the normal tissues and persists in the same Normal cells proliferate in response to growth factors produced by excessive manner after the cessation of the stimuli which evoked the one cell type to activate other cells. These external growth factors in- change.”[1] During the past 30yrs it has become exceedingly apparent clude, epidermal growth factor (EGF), fibroblast growth factor (FGF), that several viruses play significant role in multistage development of tumor growth factor alpha (TGF-a) and platelet derived growth fac- human neoplasms. Approximately 15-20% of cancers are associated tor (PDGF).These growth factors exert their proliferative action after with viral infection.[2]Oncogenic viruses contributes different steps in binding to appropriate receptor of target cells. carcinogenic process. Association of virus with a cancer of any site var- Proto-oncogenes code for proteins that regulate many functions of ies from 15 to 100%. the normal cell. Proto-oncogenes act in a dominant fashion to posi- Oral cancer is the sixth most common cancer in Asia. Incidence of oral tively regulate cell growth and differentiation. When proto-oncogenes Cancer in the Indian subcontinent is among the highest in the world. are altered, a modified gene called an is formed. These [3]According to International Agency for Research on Cancer around genes are the fundamental components of multistep tumor genesis. 77000 oral cancer cases were reported from India during the year A number of mechanism by which oncogenes activated are point mu- 2012.[4] Previously it was believed that oral cancer is a disease of old- tations of the gene, gene amplification, and gene overexpression. p53 er people of age range 50-70yrs. Recently studies have showed an in- is well established .p53 controls cell cycle pro- creasing shift towards younger age group mainly under the age of 40. gression, senescence, apoptosis, and DNA repair thus prevents tumor Oral show multiphasic and multifactorial formation. Alteration of p53 tumor suppressor gene constitutes one

Citation: Dr. Divya Raj (2019), Oncogenic Viruses in Oral Neoplasia. Int J Dent & Oral Heal. 5:5, 68-74

68 International Journal of Dentistry and Oral Health Volume 5 Issue 5, July 2019 of the most common genetic aberrations in human cancers. A second infection causes activation of growth promoting pathways or inhibi- tumor suppressor protein is retinoblastoma (Rb) protein. The Rb fam- tion of tumor suppressor products in the infected cell. These virus in- ily of proteins plays an essential role in controlling the cell cycle by fected host cells undergone genetic changes enter cell cycle and pro- governing the checkpoint between the G1 and the S phase. duce next progeny of transformed cells with capacity for autonomous Oncogenic Viruses growth. Detection of Epstein barr virus from Burkitts and Hepatitis Mode of DNA Viral Oncogenesis B virus from the hepatitis B positive human sera revealed the role of Host cell infected by DNA oncogenic viruses have one of the following viruses in human cancer in early 1970[5]. The milestone in the discovery two results of association of viruses in the development of cancer had occurred in Replication: The virus replicate in the host cell with consequent lysis of early 1980’s by the discovery of Human Papilloma virus and its associ- infected cell and release of virions ation with in humans. Isolation of human T cell leuke- Integration: The viral DNA integrate in to the host cell DNA mia virus from T cell lymphoma or patient was another major Integration results in inducing mutation and neoplastic transforma- discovery. Recently association of hepatitis C virus and human herpes tion of the host cell. Replication causes cell death but no neoplastic virus 8 has been identified to be oncogenic to humans. transformation. Immediately after infection by DNA oncogenic virus, Evans and Mueller guidelines for establishing relationship between vi- virus specific T antigens are expressed which are important for host ruses and human cancer are[9] cell transformation Epidemiologic guide lines Mode of RNA Viral Oncogenesis 1. Geographic distribution of viral infection corresponds with that of Retro viruses contain two identical strands of RNA and the enzyme tumor adjusting for the presence of known factors reverse transcriptase. Reverse transcriptase is an RNA dependent 2. Viral markers are higher in study subjects than in matched control DNA synthatase that acts as a template to synthesise single strand of subjects matching viral DNA. Single strand of viral DNA is then copied by the 3. Viral markers precede tumor development with a higher incidence DNA dependent DNA synthetase to form another strand of compli- of tumors in persons with markers than those without. mentary DNA resulting in double stranded viral DNA or provirus. Pro- 4. Tumor incidence is decreased by viral infection prevention virus gets integrated in to DNA of the host cell genome and transform Virologic guidelines the cell in to neoplastic cell. 1. Virus can transform cells in vitro The host cells which allow replication of integrated retrovirus are 2. Viral genome is present in tumor cells but not in normal cells called permissive cells. Viral replication begins after integration of 3. Virus induces the tumor in an experimental animal provirus in to host cell genome. Integration results in transcription of Hill criteria of causality proviral genes in to messenger RNA which forms components of the 1. Strength of association (Often the virus is associated with the tu- virus particle. Virion core protein from gag gene, reverse transcriptase mor) from pol gene, and envelope glycoprotein from env gene. Three com- 2. Consistency (Has the association been observed repeatedly) ponents of the virus particles are assembled at the plasma membrane 3. Specificity of association of the host cell. Virus particles are released by budding off from the 4. Temporal relationship (Does virus infection precede tumorigenesis) plasma membrane. 5. Biologic gradient ( Is there a dose response with viral load) Human Papilloma Virus 6. Biologic plausibility ( Is it biologically plausible that the virus could Human papilloma viruses are DNA . They are small non cause the tumor) enveloped double stranded DNA virus that comes under Papilloma 7. Coherence ( Does the association make sense with what is known viridae family. These viruses infect squamous epithelia of a variety of about the tumor) species. To date approximately 200 HPV types has been described.[11] 8. Experimental evidence The first evidence of the link between papillomavirus infection and Classes of Tumor Viruses cancer originated from studies of cancer induction by the cotton tail There are two classes of tumor viruses DNA viruses and RNA viruses. rabbit papillomavirus in domestic rabbits and the subsequent studies DNA tumor viruses exist in two life forms in permissive and nonpermis- performed by Peyton Rous and his associates. The viruses were first sive cells. Replication of DNA virus in permissive cell causes cell lysis visualized with an electron microscope in 1949, and their circular dou- and death. In nonpermissive cells it gets integrated in to the cells chro- ble-stranded DNA genome was demonstrated in 1963. In humans, a mosome and inactivates cell growth by regulation of p53 and retino- detailed analysis of potentially oncogenic papilloma virus began in blastoma protein (Rb). the early 1970s, with the work of Stefania Jablonska in Warsaw, who All oncogenic RNA viruses are retro viruses. The basic genes in retro considered a rare hereditary papillomatosis, epidermodysplasia verru- viruses are gag, pol and env genes. They are responsible for the pro- ciformis “as a model in studies of papillomaviruses in oncogenesis”[12]. duction of structural proteins, vorion associated enzymes, and enve- In 1983, it was first suggested that HPV might be the agent involved in lope glycoproteins. In tumor development some RNA tumor viruses the development of at least certain types of oral SCCs and in 2007, the produce some oncogenic proteins similar to proteins that control WHO stated that HPV was a cause of oral cancer’s.[13] cellular growth. Over production of these proteins stimulates cellular Classification proliferation. Second group of RNA viruses integrates their promoter Papillomaviruses are classified according to their host range and the sequences near the cellular growth stimulating gene and initiates cell relatedness of their nucleic acids. transformation. The third group encodes a protein tax that transacti- i. Papillomavirus was first named according to its natural host, e.g.Cot- vates the expression of cellular genes.[10] tontail Rabbit (Shope) Papillomavirus, Bovine Papillomavirus,Deer The transmission of oncogenic viruses can occur by horizontal trans- Papillomavirus, Human Papillomavirus (HPV), etc. mission, parenteral route or Vertical transmission. DNA or RNA viruses ii. Based on clinical prognosis of their associated lesion they can be: induce mutation in target host cell. Persistence of DNA or RNA viral low-risk HPVs, which cause benign epithelial , and high-risk

Citation: Dr. Divya Raj (2019), Oncogenic Viruses in Oral Neoplasia. Int J Dent & Oral Heal. 5:5, 68-74

69 International Journal of Dentistry and Oral Health Volume 5 Issue 5, July 2019

HPVs, e.g. HPV 16 and 18 infected lesions have high propensity for ma- population.[17]Viruses from the B2 subgroup such as HPV4 also known lignant transformation. as Gamma papillomaviruses cause cutaneous warts that can superfi- iii. According to the International Agency for Research on Cancer: cially resemble those caused by supergroup A papillomaviruses such - Group 1: HPV 16 and 18 as carcinogenic in humans; as HPV2. The remaining group of HPVs are contained within super- - Group 2A: HPV 31 and 33 as probably carcinogenic in humans; group E Mu and Nu-papillomaviruses. - Group 2B: remaining HPVs as possibly carcinogenic. Structure of HPV Genitally transmitted HPV types are classified under supergroup A The human papillomavirus (HPV) is a relatively small non-enveloped which is also known as Alpha papillomaviruses. HPV6 and 11 comes virus that contains a double-stranded closed circular DNA genome, as- in this group which are major sexually transmitted pathogens. These sociated with histone-like proteins and protected by a capsid formed viruses can also infect oral sites where they are generally associated by two late proteins, L1 and L2. The viral genome of the HPV consists [14] with benign . HPV16 and 18 are high risk viruses under of a single molecule of double-stranded and circular DNA, containing group A and they cause mucosal lesions that can progress in some in- approximately 8000 base pairs and harbouring an average of 8 open [15] dividuals to high-grade neoplasia and cancer. reading frames (ORFs).The HPV genome is divided into three regions. The second major group of human papillomaviruses are contained The first is a noncoding upstream regulatory region (URR) or long con- within supergroup B also known as Beta papillomaviruses. Viruses trol region (LCR) that has regulatory function of the transcription of from the B1 subgroup such as HPV5 cause latent infections and can the E6 and E7 viral genes. The second is an early region (E) consisting become a problem in immuno-suppressed individuals and in individ- of six ORFs: E1, E2, E4, E5, E6, and E7, which encodes no structural pro- [16] uals who have an inherited defect . Such patients can develop skin teins involved in viral replication and oncogenesis. The third is a late cancers at the site of HPV infection. B1 viruses may be involved in the (L) region that encodes the L1 and L2 structural proteins.(Fig:1) development of non- (NMSC) in the general

Mechanism of HPV Infection fest: i) Plasmid replication, which occurs in the cells of lower epitheli- um and may in turn subdivide into two phases; a) amplification of viral Oral HPV lesions can result in different clinical appearance, ranging DNA up to 50 to 400 couples/diploid genome, and b) maintenance of a from benign, hyperplastic, papillomatous, or verrucous lesions to car- constant number of couples for several cell generations. ii) Vegetative cinomatous changes. Initially, HPV infects undifferentiated prolifera- replication, which occurs in cells that differentiate from the epithelium tive basal cells, which are capable of dividing.[18]Once inside the host and involves a link between cell differentiation and viral expression of cell, viral DNA localizes into the nucleus and establishes itself as an the gene. iii) Productive replication, in which the virus is expelled from episome with a low copy number. At this stage, the viral proteins E1, the epithelial cells when they undergo desquamation and is transmit- E2, E6, and E7 transcribed from the early promoter are expressed at [19] ted by direct contact (especially genital warts), or by indirect contact. a low level. After cell division, the daughter cells retaining the viral [21] genome are pushed towards the suprabasal regions and begin to dif- HPVs are characterized by a special trophism for squamous epithelial ferentiate. This triggers a coordinated transcriptional cascade of the cells, keratinocytes. The synthesis of viral DNA and the expression of viral genome. Viral proteins, mainly E6 and E7, may disturb the normal viral genes are linked to the keratinocyte level of differentiation. The terminal differentiation by stimulating cellular proliferation and DNA normal viral replication cycle is a highly regulated process, depending synthesis by interfering with and inhibiting several cell cycle regulators both on some viral proteins codified by the viral genome and the de- to allow high-level amplification of the viral genome.[20] gree of differentiation of the infected cell. Infection usually starts in HPVs are mostly transmitted by close contact, especially sexually but the basal and para-basal cells of squamous epithelium. The changes vertical spread and self-inoculation are also recognised routes of infec- in keratinocytes from the basal layer to the surface of the epithelium, tion. After HPV inoculation, three mechanisms of infection can mani-

Citation: Dr. Divya Raj (2019), Oncogenic Viruses in Oral Neoplasia. Int J Dent & Oral Heal. 5:5, 68-74

70 International Journal of Dentistry and Oral Health Volume 5 Issue 5, July 2019 provide a suitable micro-environment for productive cell replication, sections of OSCC cases. High prevalence of koilocytes (koilocytosis) responsible for the transformation of the keratinocyte into a permis- has been reported in OSCC cases, and it has been found to be equally [22] sive cell. To activate infection, the virus must have access to the distributed among the different tumor grades[35]. A study by Cabibi et ‘generative’ compartment of the epithelium through the exposure of al shows that the sensitivity of detection of HPV infection by identifi- superficial layers to reach the basal layer where the specific integrin re- cation of koilocytes was 74% and the specificity was 72%. Presence of ceptor is present. Then, during the initial phase of infection, when the koilocytes in histopathologic sections from OSCC cases makes it a sim- virus colonizes basal and para-basal cells of the epithelium, the viral ple and reliable criteria to detect the presence of HPV in these lesions. genome undergoes episomal replication, since it is present as an ex- Many studies have further confirmed this histologic evidence of HPV tra-chromosomal fragment of circular DNA. At this stage of episomal by performing molecular biology techniques like in-situ hybridization or early replication, relatively few copies of viral DNA per host cell are and Polymerase Chain Reaction (PCR), to demonstrate HPV DNA in present. The episomal form acts as a reservoir of infected cells, which those lesions.[36] are morphologically indistinguishable from non-infected cells, and is Molecular Detection of HPV responsible for the latent status of infection. When the infection becomes productive, the viral genes are expressed There are many methods by which HPV can be detected, but every sequentially from early genes to late genes, following the epithelial method has its strength and weakness. Underlying all of the sensitive squamous differentiation, starting from basal and para-basal cells, molecular assays is the problem of contamination. Miniscule amounts where early portions of the viral genome are more active and proceed- of RNA or DNA can theoretically be carried over from sample to sam- ing to higher epithelial layers (both the intermediate and the super- ple by direct transmission on gloves or instruments, or could even be ficial) along with the formation of the complete virion.[23]The classic ‘aerosolized’. Thus, even with compulsive isolation techniques, some viral cytopathic effects may then appear: koilocytosis in particular, is contamination cannot always be ruled out. The antibodies against considered as the evident expression of a viral cytopathic effect. The HPV can be of the type IgA, IgM, or IgG, reaching maximum levels 6 to koilocytic cell shows a thicker cytoplasm at the level of the cell internal 12 months after the beginning of the infection. There is an increased membrane wall and an atypical morphologically collapsed and stellate prevalence of antibodies against proteins E7 and E4 in patients with nucleus.[24]Histologically, HPV infection may then appear as acantho- cervical intraepithelial neoplasia and with cervical carcinoma. It is pos- sis, dyskeratosis, keratinocyte multinucleation and koilocytosis.[25] sible that in the future, the measuring of the antibodies against E7 will become a marker to assess the response of a specific therapy. ELISA Mechanism of HPV Associated Oncogenesis tests for serum antibody presence to HPV have been developed which In HPV induced carcinogenesis E6 and E7 oncoproteins dysregulates correlate well with the presence of HPV DNA in cervical samples. Se- [26] cell cycle and apoptosis by acting on p53. p53 is a tumour suppres- ropositivity may be a confounding factor associated with other risk sor gene which controls G1 transition to S phase in the cell cycle at G1 factors for oral cancer, including tobacco and ethanol exposure.[37] In- check point by inducing the expression of Cyclin inhibitors p16, p21, situhybridization (ISH) involves the use of type-specific radioactively and p27 which in turn will block the Cyclin dependent kinases and pro- labelled DNA probes complementary to HPV sequences for detection. gression of cell cycle at the G1/S transition. Inactivation, degradation ISH depends on the consistency of the complementary sequence pres- or mutation of p53 gene causes increased cell proliferation, Accumula- ent in the sample, and it is known that the presence of HPV DNA in [27] tion of damaged DNA and prolonged cell survival. oral cavity samples is inconsistent. Furthermore, storage of samples Rb family of proteins governs the check point between G1 and S phase. and degradation of signal over time are also issues, as is intra observer In normal cycle hypophosphorylated Rb forms a complex with E2F variability.[38] and makes it unavailable for the DNA synthesis. Cyclin –CDK complex- Southern blot hybridization is an important research tool and has es phosphorylates Rb then E2F is released from the complex initiate been the technique generally used to classify newly identified viral transcription of S-phase genes. E7 oncoprotein inactivates Rb family types. However, the method is restricted by a time-consuming and of proteins thus causes over expression of E2F thereby produces in- labour-intensive process, as well as a reliance on radiolabeled probes [28,29] creased cell proliferation . E7 also down regulates cellular immune (isotopes). Commercial kits are not marketed for this method; rather, responses by the down regulation of Major Histocompatability Com- the process is entirely laboratory-based, using existing reagents and plex class 1 molecules, and allows HPV to persist in the infected ep- well-established methodologies. This intensive identification method ithelial cell.30 High risk HPV E7 oncoprotein causes dysregulation of therefore requires a sophisticated laboratory, with access to appropri- mitotic spindle formation and function leading to genomic instability ate reagents and personnel skilled in advanced laboratory techniques. [30,31] of the infected cell. In Southern blot hybridization, the HPV genome is extracted from a Telomerase is an enzyme that adds hexonucleotide repeats on to the specimen and the DNA chain is broken using enzymes. The product is end of chromosome telomere. Absence of telomerase leads to cell integrated into a gel, which is subjected to an electric current-a pro- senescence. HPV causes activation of telomerase there by prevents cess referred to as gel electrophoresis. The electrophoretic process shortening of telomere and prolongs life span of the HPV infected separates the DNA based on the size of each fragment. The DNA frag- .[32,33,34] cell ments separated by this method are transferred to a nitrocellulose Koilocytes – Histologic Markers for HPV membrane and hybridized with cloned HPV genomic probes. These Papillomaviruses cause epithelial proliferation characterized by epi- probes are then labelled, often using radioisotopes. The detection of thelial thickening, prominent keratohyalin granules, acanthosis, and the labelled DNA hybrids indicates that HPV is present in a given sam- sometimes hyperkeratosis. Koilocytes indicate the presence of pro- ple. Dot blot hybridization employs a simpler laboratory method than ductive HPV infection in exfoliated cells and specimens. They Southern blot but is rarely used due to its low sensitivity.[39] are squamous epithelial cells exhibiting perinuclear clearing and in- PCR is known to be a very sensitive assay for the detection of HPV DNA creased density of surrounding cytoplasm. Presence of koilocytes in in any given sample [40]. The use of consensus primers and type-specif- histologic sections is thought to represent cytopathic effect of HPV, ic primers would theoretically result in a higher detection rate, since and is considered to give a clue to the diagnosis of HPV infection. many different types of HPV would be identified. Quantitative PCR Presence of koilocytes has been documented in smears and tissue utilizes a fluorescent probe that is cleaved upon each round of amplifi-

Citation: Dr. Divya Raj (2019), Oncogenic Viruses in Oral Neoplasia. Int J Dent & Oral Heal. 5:5, 68-74

71 International Journal of Dentistry and Oral Health Volume 5 Issue 5, July 2019 cation by the DNA polymerase, and the degree of fluorescence in the lymphoma. Oral epithelial tumors that have an association with Ep- reaction mixture is then measured. stein–Barr virus include lymphoepithelioma like carcinoma, salivary The great variation in HPV prevalence found in OSCCs in different stud- gland lymphoepithelial carcinoma, multiple or bilateral Warthins tu- ies may be not only due to the differences among the analysed popula- mor (cystadenolymphoma) of the parotid gland, tonsillar carcinoma, tion, but also due to the differences in the samples tested highly undifferentiated and oral hairy .[46] ( formalin-fixed or fresh , exfoliated fresh cells), the methods Oral is associated with immunosuppression and main- of DNA extraction, and most importantly the HPV detection methods ly HIV infection. The oral hairy leukoplakia lesion appears on the lateral used [41]. borders of the tongue as a whitish hyperkeratotic hair-like growth that Prognosis of HPV Associated OSCC cannot be rubbed off. Biopsies of hairy leukoplakia lesions show epi- Recent data suggest that a positive HPV status represents an import- thelial hyperplasia and mild inflammation, and Epstein–Barr virus can ant prognostic factor and is associated with a favourable outcome be detected in the superficial layers of the epithelium. Epstein–Barr in . Many studies confirmed that HPV-positive virus-infected periodontal pockets in intimate contact with the lateral OSCC have a better prognosis compared with those that are HPV neg- borders of the tongue are the most likely source of the viral infection. ative. HPV positive OSCC arises through a different mechanism or ex- Malignant transformation of hairy leukoplakia has not been reported. hibits less genetic instability shows a lower degree of aneuploidy and Most oral hairy leukoplakia lesions respond well to high-dose acyclo- a tendency to have fewer chromosomal aberrations, when compared vir and topical treatment with gentian violet shows promising results. to HPV-negative cancer.[42,43] Proliferative verrucous leukoplakia affecting gingiva and other oral sites has a high risk of malignant transformation to squamous cell car- Therapeutic Possibilities cinoma and may be related to the Epstein–Barr virus. It was first shown in cervical cancer cells that if viral RNA transcript EBV has the ability to establish a latent infection, which means a si- was blocked by antisense RNA, the expression of the HPV gene could lent state of viral infection characterized by the low expression of viral be suppressed, which may reduce the growth of cancer cells. Only one genes and minimal cytopathic effects or production of infectious virus. study has addressed the possibility of preventing growth of human EBV infects two types of target cells: epithelial cells in the oro/naso- cancer cells by expression of antisense E6/E7. Von Knebel Doeberitz and/or , and the B-lymphocytes.EBV encodes et al. cloned E6 and part of E7 region of HPV 18 in a eukaryotic expres- several viral proteins that have transforming potential, including EBV sion vector in the reverse orientation with respect to the promoter. latent membrane proteins 1 and 2 (LMP1 and LMP2) and EBV nuclear Expression vector was introduced into C4-1 cells, a cervical antigens 2 and 3 (EBNA2 and EBNA3).LMP1 is essential for the ability line that expresses HPV 18 genes. On expression of antisense E6/E7, of EBV to immortalize B cells.LMP1 also upregulates the expression of the cells showed significant changes in the phenotype; the cell size numerous antiapoptotic and adhesion genes and activates the expres- and colony size were reduced both on plastic and in soft agar. sion of matrix metalloproteinase-9 (MMP-9), and fibroblast growth Simple antisense technology was later superseded by ribozymes. Ri- factor-2 bozymes directed against E6/E7 transcribed patients are effective in EBV has been implicated in the etiology of oral cancer by some authors reducing the growth rate of HPV containing cervical cancer HeLa cells. but there is controversial results. Ching-Yu Yen et al detected EBV in- An added advantage is that ribozymes can cut the target RNA so that fection and gene expression in oral cancer from patients in Taiwan there is a permanent reduction in the pathological RNA. The most re- by microarray analysis revealed that the majority of the specimens cent version of this therapy consists of siRNA, a molecule that also (82.5%) were EBV-positive.[47]Zheng et al documented that moderately recognizes viral RNA targets and is also effective in silencing their ex- differentiated OSCC of tongue had higher EBV than well differentiated pression. one and this indicates the correlation between EBV and differentiation A major advancement was the recent introduction of two vaccines for of tongue cancer.[48] the prevention of HPV-associated diseases. These vaccines consist of Virus Type 1 (Hsv 1) virus-like particles that contain the L1 protein from several HPV types. Each vaccine has been tested in controlled clinical trials and is effective Herpes simplex virus infections are very common and affect a high per- in reducing the incidences of cervical abnormalities. But their oral ef- centage of all human populations. In 1962, Schneweiss identified two fects are yet not yet known. Currently these vaccines are recommend- serotypes, subsequently confirmed by Nahmoas and Dowdle. Where- ed only in adolescent females. Their use in males and older females is as HSV-1 is found predominantly in oropharyngeal infections, HSV-2 still to be established.[44] has a strong predilection for anogenital sites. The first animal model that demonstrated that HSV could be a co-car- Epstein–Barr Virus cinogen was introduced by Southam et al.[49] Herpes simplex actually Epstein-Barr virus (EBV) is named after Michael Anthony Epstein and belongs to a family of eight related viruses, including herpes simplex Yvonne Barr, who discovered and documented the virus in 1964. It virus types 1 (HSV-1) and 2 (HSV-2), varicella-zoster virus, Epstein-Barr is a virus of herpes family. The human herpes virus family consists of virus, and cytomegalovirus. All of these organisms are double-strand- three subfamilies, alpha,beta, and gamma. EBV belongs to the gam- ed DNA viruses that affect the skin, mucous membranes, and, less fre- ma subfamily, which is split into two genera, lymphocryptovirus and quently, the esophagus and brain. Herpes simplex virus (HSV) type1 rhadinovirus. EBV is the prototype for the lymphocryptovirus because (HSV-1) and the closely related HSV type 2 (HSV-2) have enveloped, it latently infects B-lymphocytes[45] spherical virions. The genome of HSV-1 is densely packaged in a liq- The virus consists of a linear double-stranded DNA core surrounded by uid-crystalline, phage-like manner in a 100-nm icosahedral capsid.[50] a nucleocapsid and an envelope that contains glycoproteins. Epstein– Herpes simplex virus type 1 (HSV-1) is an important pathogen that Barr virus is involved in a great variety of cancers. In the oral cavity, causes a variety of clinical manifestations in humans. It has the ability Epstein–Barr virus has been identified in Hodgkins lymphoma, natural to remain latent in host neurons for life, and can reactivate to cause le- killer cell ⁄ T-cell lymphoma, Burkitts lymphoma, cyclosporine-related sions at or near the site of initial infection. One of the major features of post-transplant lymphoproliferative disorder, post-transplant diffuse HSV infection is the ability of the virus to remain latent in the sensory B-cell lymphoma, follicular lymphoid hyperplasia and plasmablastic ganglia. Following HSV infection, viral replication occurs in the oral or

Citation: Dr. Divya Raj (2019), Oncogenic Viruses in Oral Neoplasia. Int J Dent & Oral Heal. 5:5, 68-74

72 International Journal of Dentistry and Oral Health Volume 5 Issue 5, July 2019 genital mucosa and the virus enters sensory nerve endings innervating squamous cell carcinoma tissues. Some tumors are associated with the mucosal membranes. Reactivation from the latent state results papillomaviruses and some with viruses of the herpes family however; in productive infection that ultimately leads to the lytic (productive) the exact role of these viruses must still be evaluated carefully. These destruction of distal epithelial cells. During the lytic cycle of the virus viruses may provide targets for therapy and for diagnostic tests and in cultured cells, regulation of HSV-1 replication occurs mainly at the may widen our understanding of the mechanisms by which the tumors transcriptional level and involves the coordination of three phases of develop. Vaccines are designed strictly for prevention of such viral in- gene expression. This process involves condensation of the chromatin fections which may be involved in cancers of the head and neck. Large on the lytic gene promoters followed by inactivation.[51] prospective randomized trials are needed to document the clinical HSV skin infections are usually located in the labial, genital, or anorec- usefulness of these vaccines against oral cancer. tal areas. Of the two serotypes, HSV-1 infection is primarily pharyn- References geal and HSV-2 infection is primarily genital, though HSV-1 has been found in genital lesions and HSV-2 in oral lesions. The transforming 1. Kumar ,Abbas,Fausto.Pathologic basis of disease.Elsevier; 7th Edi- mechanisms of HSV 1 and 2 remain obscure. The viruses have not been tion: 269 shown to encode an oncogene or related gene and furthermore the 2. MargaraetE,Drubin ML, MungerK.Viruses associated with Human transforming regions of the genome are not retained in transformed cancer.Biochimica et biophysica acta2008;127-150 cells. 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Citation: Dr. Divya Raj (2019), Oncogenic Viruses in Oral Neoplasia. Int J Dent & Oral Heal. 5:5, 68-74

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