**The Role of Human Papillomavirus in Pre-Cancerous Lesions and Oral Cancers**

Danilo Figueiredo Soave, Mara Rubia Nunes Celes, João Paulo Oliveira-Costa, Giorgia Gobbi da Silveira, Bruna Riedo Zanetti, Lucinei Roberto Oliveira and Alfredo Ribeiro-Silva

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55943

**1. Introduction**

[61] Wang S, Wei H, Wang N, Zhang S, Zhang Y, Ruan Q, et al. The prevalence and role of human papillomavirus genotypes in primary cervical screening in the northeast of

240 Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective

[62] Zur Hausen, H. (2006). Infections causing human cancer. Weinheim (Germany): Wi‐

China. BMC Cancer. 2012 May;12(160).

ley-VCH Verlag, pp. 145–243.

The head and neck squamous cell carcinomas (HNSCC) are the sixth most frequent malignancy worldwide. It is properly established as heterogeneous solid tumor, composed by cells with different phenotypic features with malignant potential. Oral squamous cell carcinoma (OSCC) is a significant subset of the worldwide burden of HNSCCs. It is essential the understanding of the OSCC biology and biological behavior of pre-cancerous conditions and pre-cancerous lesions that may be responsible for malignant transformation. Heterogeneity in prevalence and anatomic distribution are associated to demographic differences in the habits of exposure tobacco and alcohol. The use of tobacco and alcohol are often established as risk factors for OSCC, but this phenomenon could also emerge in individuals not exposed to them. As OSCC, the pre-cancerous lesions also present a strict connection to tobacco consumption. However, a relationship between alcohol carcinogenic effect and pre-cancer lesions are not clear. These populations that develop the pre-cancer lesions or OSCC in the absence of prior contact with risk factors suggest that others factors can play a role in head and neck carcinogenesis. There is a longstanding analysis, over the past 2 decades, whether the human papilloma virus (HPV) infection could have a role in the OSCC carcinogenesis. HPV were first established as cancer development agent in cervical cancer, succeeding reports established the HPV infection in mucosal tissues of the oral cavity upper gastrointestinal tract, anogenital tract. In cervical cancer the categorization subdivided the HPV types into low-risk high-risk types, only the types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, and 58 are consistently grouped as high risk. The high-

© 2013 Soave et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

risk types 16 and 18, as in the cervical and anogenital cancer, are the most common entities detected in pre-cancerous and HNSCC lesions. Miller & Johnstone [1] describe that likelihood of detecting HPV, comparing pre-cancerous lesions and HNSCC to normal epithelium, was three times higher in pre-cancerous lesions and four a five times higher in HNSCC. In despite of large number of studies, the accurate role of HPV in the HNSCC development and pro‐ gression has been controversial so as in OSCC. HPVs are a circular virion enclosed in a small capsid. The carcinogenic process occurs through the HPV-DNA integration into host cell. Usually, the viral oncoproteins codified by HPV-DNA, leads a functional alteration in p53 and pRb pathways, and consequently genomic instability. However, the oncoproteins expression alone is not sufficient to induce neoplastic transformation suggesting the requirement of supplementary genetic modifications. Increased understanding of the role of HPV antigens in neoplastic pathogenesis confirms the HPV as an etiological agent for cancers and, the knowl‐ edge of HPV cancer biology consequently will provide the development of preventive vaccines and antiviral treatment. The HPV vaccines have been formulated as a result of core technolo‐ gies implementation that is able to construct virus-like particles (VLPs) equivalent to natural virions but, at the same time, are not capable to induce an infectious process. In addition, in this chapter we will discuss the HPV relationship with the pre-cancerous lesions and OSCC. The present data summarize the knowledge regarding the epidemiology, behavior, biology, malignant transformation mechanisms, and prognosis of HPV infection.

provided by Syrjänen et al. [9-11] firstly suggested a link among HPV infection, HNSCC and OSCC, through the examination of 40 biopsy specimens. These authors described morpho‐ logical alterations caused by HPV infection in 16 cases; this observation gives supports to HPV involvement in the development of OSCC. However, the confirmatory evidence of HPV-DNA in the oral lesions was presented only in 1985 [6,12]. Although the presence of HPV DNA has been suggested as a possible etiologic factor of oral pre-cancer and cancer, this association has

The role of Human Papillomavirus in Pre-Cancerous Lesions and Oral Cancers

http://dx.doi.org/10.5772/55943

243

HPV represent a group of DNA viruses that was recently recognized to form their own family, Papillomaviridae that initially, together with polyomaviruses, was grouped in the Papova‐ viridae family [13]. They are an ancient family of pathogens and are known to infect epithelial tissues of amphibians, reptiles, birds and mammals [14]. The virus is formed by a nonenveloped icosahedral capsid with circular double-stranded DNA [15-16]. The genome is small, comprising to 8.000 base pairs, but it is complex, composed of three distinct regions: early region (E), late region (L) and upstream regulatory region (URR) or long region control

The E region contains from seven to eight genes (E1, E2, E3, E4, E5, E6, E7 and E8), of which E1 is related with viral replication, E2 with viral transcription and DNA replication, E4 with maturation and alteration of extracellular matrix cell and E5, E6 and E7 are involved in cellular transformation. The E3 and E8 genes have been recently described only in a few HPV types but their function is unknown [16-18].The L region containing two genes, L1 and L2, which encode structural proteins necessary for viral capsid formation in the final stages of replication. Both E and L are coding region therefore called open reading frames (ORF), however the region URR does not fit in this description because it is a non-coding region. The URR region is found between E and L region and contain promoter and enhancer DNA sequences critical to regulate

Based on phylogenetic analysis, the HPV is classified into genera (alpha, beta, gamma, mu and nu), species and types [15]. The classification of HPV types is based mainly on analyses of the L1 gene, which is the most conserved gene in all known papillomaviruses. When the DNA sequence of the L1 ORF differs by more than 10% from the closest known virus type, a new papillomavirus is recognized. Differences between 2% and 10% homology define a subtype and less than 2% a variant. A viral variant can differ between 2% in coding regions and 5% in non-coding regions [13,15]. Currently, approximately 150 different types are recognized and 120 HPV types are fully sequenced [18]. Types classified as members of the same species with approximately 80-90% of similarities trend to share biological properties such as the tissue

According to their tropism, the HPV also can be classified as cutaneous and mucosal type. The cutaneous type are associated with skin lesions, being HPVs 1, 2 and 4 the most prevalent in common and plantar warts, and the types 5, 8, 9, 12, 14, 15, 17, 19-25, 36, 46 and 47 the most

viral replication and transcription by both viral and cellular genes [19].

tropism, disease manifestation, and pathogenicity [14].

not been as reliable as in cervical cancers.

(LCR).

**3. HPV biology: General considerations**
