Abstract Oral potentially malignant disorders (OPMDs) are conditions with abnormal changes of the oral mucosa that can potentially transform into oral squamous cell carcinoma (OSCC). Due to a rather high detection rate of human papillomavirus (HPV) in head and neck cancer particularly oropharyngeal carcinoma, HPV has been postulated as a plausible cause of OPMDs and OSCC development. A considerable number of studies have shown HPV can be detected in OSCC and OPMDs including oral leukoplakia (OL) and oral lichen planus (OLP). The detection rate nevertheless varies depending on the study design, data collection, and detection method. One of the most common methods for HPV detection is a polymerase chain reaction (PCR) analysis of E6 gene. However, the detection of the E6 gene may only reflect a bystander effect where HPV could exist in human tissues without host’s genomic integration. Genomic integration of HPV could be detected by various means including analyses of mRNA or protein expression in tissues of interest or detection of E2 gene since recent data have shown that E2 gene is disrupted upon genomic integration of the virus. In this review, we elaborated the nature of OPMDs and OSCC and emphasize on HPV infection and integration in OPMDs since detection of HPV at the early stages of oral cancer development may lead to alternative preventive and treatment measures for patients.

Keywords: Genomic integration, Human papillomavirus, Oral leukoplakia, Oral lichen planus, Oral potentially malignant disorder, Oral squamous cell carcinoma, Malignant transformation

Funding: Research Funding for graduate students and Faculty Research Grant, Faculty of Dentistry, Chiang Mai University, Thailand.

Citation: Tangthikul S., Tachasuttirut, K., Pongsiriwet, S., Lekawanvijit, S., Kitkumthorn, N., Lapthanasupkul, P., and Iamaroon, A. 2025. The role of human papillomavirus in oral potentially malignant disorders and cancer: A review literature. Natural and Life Sciences Communications. 24(2): e2025028.

ORAL POTENTIALLY MALIGNANT DISORDERS

Oral potentially malignant disorders (OPMDs), also called potentially premalignant oral epithelial lesions, are clinical conditions with abnormal oral mucosal tissues that can potentially transform into oral cancer, particularly oral squamous cell carcinoma (OSCC) (Warnakulasuriya et al., 2021). According to 5th edition of the World Health Organization Classification of Tumors of the Head and Neck, OPMDs encompass a wide variety of oral conditions including oral leukoplakia (OL), oral erythroplakia, oral submucous fibrosis, oral proliferative verrucous leukoplakia (PVL), oral lichen planus (OLP), oral lichenoid lesions, oral lupus erythematosus, oral graft versus host disease, actinic cheilitis, smokeless tobacco keratosis, palatal lesions in reverse smokers, and inherited genetic disorders including oral dyskeratosis congenita, Fanconi anemia, xeroderma pigmentosum, Li Fraumeni syndrome, Blooms syndrome, ataxia telangiectasia and Cowden syndrome (World Health Organization, 2022). OL is the most commonly encountered OPMD in the oral cavity (Warnakulasuriya et al., 2021). Each OPMD exhibits a different transformation rate into cancer, depending on its clinical features and level of oral epithelial dysplasia. Oral erythroplakia has the greatest likelihood of transforming into OSCC, occurring in approximately 50% of cases. Non-homogeneous OL is more likely to transform into OSCC than homogeneous OL, ranging from 3–17% (Awadallah et al., 2018; Warnakulasuriya et al., 2021; Yang et al., 2018). OLP lesions, particularly the atrophic and erosive/ulcerative types, have a transformation risk of approximately 1% (Awadallah et al., 2018). Histopathologically, OPMDs with mild to moderate dysplasia have an OSCC transformation risk estimated from the logistic model as 10.3%, compared with severe dysplasia have a high risk of 24.1% (Mehanna et al., 2009).

Previous studies have identified factors contributing to malignant transformation of OPMDs including host and environmental factors. Host factors refer to patient’s own immune and genetic predisposition. Significant environmental factors include smoking, alcohol consumption, betel nut chewing, and infection with the human papillomavirus (HPV) (Awadallah et al., 2018; Porter et al., 2018).

ORAL CANCER

Cancer is a serious global health issue. Among cancer cases, head and neck cancer ranks as the seventh most significant cancer in terms of occurrence and mortality. About 890,000 individuals are newly diagnosed with head and neck cancer annually, resulting in more than 450,000 fatalities. Head and neck cancer comprises cancers affecting the nasopharynx, nasal sinuses, oropharynx, hypopharynx, larynx, and oral region (Barsouk et al., 2023). Within this category, oral cancer, which includes malignancies of the lip, tongue, gingiva/alveolar mucosa, mouth floor, palate, buccal/labial mucosa and vestibule, and retromolar area, and other unspecified oral regions, is recognized as a significant health ailment in various regions worldwide, including South and Southeast Asia (Warnakulasuriya, 2009).

More than 90% of cancer of the mouth are attributed to OSCC (Badwelan et al., 2023). The risk of OSCC increases with age, typically affecting those aged more than 40 years (Pytynia et al., 2004). The average age of diagnosis is within the fifth and sixth decades in Asia but in the seventh and eighth decades in North America (Warnakulasuriya, 2009). Moreover, a notable increase in the prevalence among younger individuals has been documented in several regions, globally (Pytynia et al., 2004). OSCC exhibits a sex disparity, occurring with a male-to-female ratio of 2.1:1. This ratio varies across regions, ranging from 1.4:1 in northern Africa, western and southern Asia, and Oceania to 5.2:1 in Europe (Komolmalai et al., 2015). Regarding affected sites, the tongue is most affected globally, followed by the mouth floor, the soft palate, the gingiva, the buccal mucosa, and the hard palate (Tan et al., 2023). Among Asian population, the prevalence of OSCC at buccal mucosa is more common due to betel quid/tobacco chewing habits (Warnakulasuriya, 2009).

OSCC typically exhibits distinctive histopathologic features such as an elevated nuclear-to-cytoplasmic ratio, keratin pearls, heightened mitotic figures, dyskeratosis, prominent nucleoli, nuclear chromatin changes, and pleomorphism. Additionally, there appears to be increased mitoses and necrotic areas in cases with poorly differentiated SCC (Ahmed et al., 2019). In many countries, the prognosis of individuals diagnosed with oral cancer remains unfavorable. Globally, the five-year survival rate for oral cancer is more than 50% and is expected to be lower in developing countries. Nonetheless, this survival rate could be enhanced through early detection (Saka-Herrán et al., 2021).

Typically, the prognosis worsens with disease advancement and inaccessibility of the tumors. Women generally exhibit higher survival rates than men for both tongue and oral cavity cancers. The TNM stage upon diagnosis notably impacts the likelihood of surviving five years. For instance, in cases of mobile tongue cancer, the five-year survival rate plunges from 80% for stage 1 to a mere 15% for stage IV (Warnakulasuriya, 2009). Additionally, in southeast Asia particularly Thailand, patients with OSCC have a less favorable survival rate than those in Western countries. For example, in Thailand, the five-year survival rate for oral cancer is 27.4%, notably higher in the younger population. In addition, the five-year survival rate was higher among female patients (33.7%) than male patients (25.3%) (Komolmalai et al., 2015).

Extensive research has explored the etiology, risk factors, diagnosis, and treatment of OSCC. Tobacco smoking and alcohol consumption are well-established risk factors for OSCC, contributing to genetic mutations and increasing the risk of malignant transformation (Warnakulasuriya, 2009). Furthermore, betel quid chewing, a common practice in certain regions, has been strongly linked to OSCC development (Acharya et al., 2021). HPV infection, particularly HPV types 16 and 18, has been recognized as an emerging risk factor for oral and oropharyngeal cancers (Sri et al., 2021).

HUMAN PAPILLOMAVIRUS

HPV is a tiny virus with a double-stranded, circular genome of approximately eight kilobases. HPVs exclusively target and infect epithelial cells, demonstrating a strict epitheliotropic nature. HPV genome is divided into three essential parts as shown in Figure 1 (Harden and Munger, 2017; Pešut et al., 2021). 1) The early (E) region, containing E1, E2, E4, E5, E6, E7, and E8 genes, plays a significant role in DNA replication, cellular transformation, and controlling viral transcription. 2) The late (L) region, containing L1 and L2 genes, encodes structural proteins and is involved in virion assembly. 3) The long control region (LCR), also known as the upstream regulatory or non-coding region, is crucial in DNA replication and viral transcription. LCR also plays a significant role in controlling self-replication of DNA and decoding of viral information. Detailed information about each viral gene or open reading frame (ORF) and the functions of the viral proteins is shown in Table 1.

Figure 1. Schematic representation of HPV16 genome (Modified from Pešut et al., 2021). E1-7 = early region genes 1-7, L1-2 = late region genes 1-2, LCR = long control region gene.

Table 1. Open reading frame (ORF) and the functions of viral proteins (Harden and Munger 2017; Pešut et al. 2021; Syrjänen 2018).

HPV can be classified into two groups: high-risk and low-risk HPV based on the characteristics of the E6 and E7 oncoproteins. E6 and E7 oncoproteins of the high-risk HPV have a greater ability to interact with the host’s tumor protein p53 encoded by TP53 gene and retinoblastoma transcriptional corepressor 1 (RB1) encoded by pRb gene than those of the low-risk HPV. These differences in protein interactions contribute to the oncogenic properties of high-risk HPV (Folliero et al., 2023).

High-risk HPV types include 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 70, known to cause various cancers, for example cervical cancer and other cancers in the anogenital and head and neck regions. Low-risk HPV types include 6, 11, 42, 43, and 44, commonly associated with the development of benign genital warts (Lacey et al., 2020; Gargano et al., 2023).

HPVs can be detected in various body parts, such as the skin, female genital tract, cervix, urethra, male genital organs, anus, oropharynx, and oral cavity. The transmission of HPV to the oral cavity can occur through different means, including sexual contact, self-inoculation, and exposure during childbirth through the mother’s vagina. Behaviors particularly oral sex and kissing have also been linked to HPV transmission (Wierzbicka et al., 2023).

HPVs specifically target and infect the squamous epithelium. HPV expression is related to the level of keratinocyte division (Campisi et al., 2007; Raff et al., 2013). HPV infection typically begins with virions entering the damaged mucosal epithelial tissue and skin, specifically targeting the basal cells. In the early stage of the HPV life cycle, the viral DNA remains within the basal cells as a plasmid, with the E1 and E2 proteins being firstly expressed and playing a role in viral genome maintenance. The infected cells undergo division and migrate to the suprabasal cell layers, triggering gene expression in general, capsid formation, and the production of the E4 and E5 proteins, leading to viral particle assembly. Subsequently, E4 protein disrupts the arrangement of cytokeratin filaments, enabling discharged viral particles to escape from infected epithelial cells and transmit to the surrounding tissues (Campisi et al., 2007).

Significantly, specific E6 and E7 proteins, known to link to the cancer-causing potential of HPV, help to regulate the viral life cycle and enable the virus to establish long-term residence within host cells. In addition, these proteins also promote cancer development by interfering with the normal expression of cellular genes. Specifically, the HPV E6 protein helps to break down p53, a protein that regulates cell growth and triggers programmed cell death in genetically insulted cells (Szarka et al., 2009; Raff et al., 2013; Pierangeli et al., 2016). Furthermore, the E6 protein disrupts the function of the other proteins involved in regulating cell death, such as BCL2 antagonist/killer 1 (BAK1) and caspase 8 (CASP8) (Harden and Munger, 2017; Shimada et al., 2020). Moreover, the E6 protein has been found to inhibit the apoptosis of abnormal cells and stimulate telomerase activity, prolonging the lifespan of abnormal cells. The E7 protein, on the other hand, inhibits pRb, crucial in suppressing cell division (Harden and Munger, 2017; Pešut et al., 2021). The binding of the E7 protein to pRb disrupts the pRb-E2F complex, leading to the release of E2F, a transcription factor that promotes gene transcription. As a result, DNA synthesis is enhanced, G to S cell cycle progresses, and ultimately the division of the infected cells become uncontrolled (Haręża et al., 2022). Therefore, the actions of the HPV E6 and E7 proteins inhibit the apoptosis of abnormal cells and promote unrestricted cell proliferation.

HPV particles invade cells within the basal layer of the cervical epithelium, typically through microtrauma. During infection, early genes are initially activated, which regulate viral replication and transcription. In cases of persistent infection, abnormal changes occur in the cells of the parabasal layer. Nonetheless, the productive viral life cycle persists, and the region of cell growth expands as cervical intraepithelial neoplasia (CIN) advance from CIN1 to CIN2. If the host’s immune system fails to eliminate the viral infection, allowing it to persist over many years, precancerous lesions and, eventually, cancer can develop (Pešut et al., 2021). Most HPV infections are asymptomatic and self-resolved within 12-24 months through innate and adaptive immune responses. However, various contributing factors, including immunosuppression, genetic factors, dysbiosis, and chronic stress, can enable approximately 10% of persistent infection (Jayshree, 2021; Ye et al., 2023). Over time, infection with high-risk HPV types results in uncontrolled cell growth without the capacity to repair genetic abnormalities, causing genetic instability, cell immortalization, and the loss of cellular polarity. Ultimately, this leads to the malignant transformation of host cells. Figure 2 illustrates host’s cells infected by HPV that completely integrate into the cellular genomes and develop to cancerous cells (Pešut et al., 2021).

Figure 2. Diagram illustrating the transformation of human papillomavirus-infected cells into cancerous cells (Rautava and Syrjänen, 2012).

HPV-RELATED OPMDS

Infection with HPV, particularly types 16 and 18, has been identified as a significant risk factor for developing some types of cancer, including SCC in the anogenital region, oropharynx, and oral cavity (Syrjänen, 2018). Recent research suggests that contracting HPV in the oral cavity may be a contributing factor in developing some lesions with an increased risk of oral cavity cancer. This correlation is attributed to the presence of substantial HPV infection within these particular lesions (Chen and Zhao, 2017). Usually, about 12% of cases have HPV infections in the oral tissues, which are often cleared within two years in those with healthy immune systems. However, if the HPV infection persists for longer than two years, the virus can potentially encourage aberrant alterations in the host’s cells, allowing cancer to develop over an extended period (Syrjänen et al., 2011; Awadallah et al., 2018; Syrjänen, 2018). Notably, HPV infections are detected about 2–3-fold more often within OPMDs than in normal tissues (Miller and Johnstone, 2001). OPMDs related to HPV infection include OL and OLP (Syrjänen et al., 2011).

HPV-related oral leukoplakia

OL, defined as white patches that cannot be scraped off and cannot be diagnosed as any other diseases within the oral cavity, is typically asymptomatic and often incidentally detected when patients visit dentists (Warnakulasuriya et al., 2021). OL can be found in 1–5% of the entire population and has a potential malignant transformation rate of 0.13–40.8%. OL is commonly found in individuals aged more than 30 years and predominantly affected males more than females (Aguirre-Urizar et al., 2021).

Factors contributing to an increased risk of malignant transformation for OL are described as follows,

1)    Non-homogeneous OL has an up to sevenfold greater likelihood of malignant transformation than homogeneous OL. Furthermore, non-homogeneous OL with white mixed with red areas, also known as erythroleukoplakia, has an up to 21% risk of malignant transformation (Rodriguez-Lujan et al., 2022).

2)    Lesions larger than 200 mm2 have a fivefold higher likelihood of progressing into cancer (Cerqueira et al., 2021).

3)    Lesions with dysplastic features upon histopathological examination are more prone to transformation into cancer than non-dysplastic lesions (Yang et al., 2018).

Dysplasia of oral mucosal cells can be found in 5–25% of OL cases (Neville et al., 2023). Currently, the degree of dysplasia in surface epithelial tissue, as indicated by histopathological examination, serves as an indicator of the likelihood of transformation into cancer for lesions at a recognized risk for developing oral cavity cancer (Yang et al., 2018). The significance of the severity of dysplasia lies in the fact that lesions with a higher degree of dysplasia are more likely to transform into cancer (Speight et al., 2018; Yang et al., 2018).

Previous studies have observed an association between OL and HPV infection since 1986 (Syrjänen et al., 1986). The likelihood of detecting HPV within OL has been reported to range from 18-41% shown in Table 2 (Ostwald et al., 2003; Campisi et al., 2004; Szarka et al., 2009; Pierangeli et al., 2016). Furthermore, a 2011 systematic literature review by Syrjänen et al. (2011) revealed that HPV was associated with OL, with an odds ratio (OR) of 4.03. In addition, Kaewmaneenuan et al. (2021) found association between OL and HPV up to 19.8%. However, the issue of the relationship between HPV and OL remains unclear. While some studies have identified a correlation between HPV infection and OL (Sand et al., 2000; Ostwald et al., 2003; Campisi et al., 2004; Llamas-Martínez et al., 2008; Khanna et al., 2009; Majumder et al., 2009; Szarka et al., 2009; Mathew et al., 2011; Sikka and Sikka, 2014; Kaewmaneenuan et al., 2021), others have not (Khovidhunkit et al., 2008; Saghravanian et al., 2011; Bhargava et al., 2016; Bhosale et al., 2016; Wu et al., 2019). Moreover, previous studies on the infection rate of types of HPV-related OL have shown that PVL exhibits the highest prevalence. Among all OL types, PVL is also known to have the highest rate of malignant transformation (Palefsky et al., 1995; Nielsen et al., 1996). Interestingly, homogeneous OL shows the higher rate of HPV infection than non-homogeneous OL, while non-homogeneous OL has the higher rate of malignant transformation than that of homogeneous OL (Nielsen et al., 1996; Campisi et al., 2004; Feller and Lemmer, 2012). In addition, long-term investigations have found no significant different rates of malignant transformation between HPV-related and HPV-unrelated OL (Wu et al., 2019; Bukovszky et al., 2023). Nonetheless, due to many up-to-date reports of the correlation between OL and HPV, these could suggest HPV as one of the possible etiologic factors of OL.

Table 2. HPV-related oral leukoplakia.

Note: HPV* = HPV-16/18 and/or other types.

HPV-related oral lichen planus

OLP is a chronic inflammatory condition of the mucous membranes, caused by an abnormal immune response (Chen and Zhao, 2017). Previous studies have reported that OLP affects approximately 1-2% of the population. The clinical characteristic of OLP lesions is typically white lace-like, also known as Wickham’s striae. As the disease progresses, the lesions become erosive and ulcerated. The most common location of OLP is buccal mucosa, often occurring bilaterally (Warnakulasuriya et al., 2021).

OLP lesions have an approximately 1% rate of malignant transformation (Awadallah et al., 2018). The risk of cancer progression is higher in patients who smoke, consume alcohol, are infected with the hepatitis C virus, have atrophic or erosive/ulcerative types of OLP, or exhibit dysplastic features in oral mucosal histopathological examinations (Aghbari et al., 2017). The reason OLP is susceptible to HPV infection is its chronic inflammatory nature, which is linked to the body’s immune system (Pierangeli et al., 2016). Additionally, the erosion of the surface tissue of the lesions provides a pathway through which HPV can easily infiltrate and embed itself within the layers of the skin (Syrjänen et al., 2011; Mattila et al., 2012; Pierangeli et al., 2016). Moreover, patients experiencing a burning sensation when consuming spicy foods often require prolonged steroid use to treat the lesions, which can suppress the body’s immune system (Syrjänen et al., 2011; Mattila et al., 2012).

Previous studies have found that HPV is more frequently detected in OLP than in normal tissues. To clarify, a 2011 systematic literature review by Syrjänen et al. reported an association between HPV and OLP, with an OR of 5.12 (Syrjänen et al., 2011). Recently, a systematic review by Vijayan et al. (2021) reported the higher detection rate of HPV in erosive/atrophic OLP, compared to non-erosive/atrophic type. Additionally, there was no differences in the malignant transformation rate between HPV-related and HPV-unrelated OLP. Numerous studies shown in Table 3 conducted since 2003 have established a correlation between OLP and HPV infection, including HPV types 16, 18, and unspecified. HPV Infection has been detected in more than 15% of OLP cases (Sand et al., 2000; OFlatharta et al., 2003; Ostwald et al., 2003; Campisi et al., 2004; Razavi et al., 2009; Szarka et al., 2009; Yildirim et al., 2011; Mattila et al., 2012; Pol et al., 2015; Sahebjamiee et al., 2015; Zendeli-Bedjeti et al., 2017; Liu et al., 2018). Recently, Kaewmaneenuan et al. (2021) found that 18.6% of HPV16 and HPV18 were associated with OLP specifically in northern region of Thailand. The other studies, however, found no correlation between HPV infection and OLP (Khovidhunkit et al., 2008; Arirachakaran et al., 2013; Gomez-Armayones et al., 2019). The discrepancy of the results may be due to differences of genetics, ethnics, geography, and sexual behaviors of patients with OLP. Collectively, the majority of studies have detected HPVs in OLP with variable rates. HPV may, therefore, be considered as a causative risk of OLP.

Table 3. HPV-related oral lichen planus.

Note: HPV* = HPV-16/18 and/or other types. 

HPV-RELATED ORAL SQUAMOUS CELL CARCINOMA

Several meta-analyses and observational studies have investigated the link between HPV and OSCC. A well-known meta-analysis by Miller et al. (2001) included 94 studies on HPV and oral cancer. The results of the analysis of 4,680 samples demonstrated a greater likelihood of detecting HPV in oral tissues with precancerous and cancerous lesions than with normal mucosa. Specifically, the HPV detection rate was 10% (95% confidence interval [CI] = 6.1–14.6%) in normal oral mucosa, markedly lower than the 46.5% (95% CI = 37.6–55.5%) in OSCC. The pooled OR comparing the prevalence of HPV infection between normal mucosa and OSCC was 5.37 (Miller and Johnstone, 2001). Another meta-analysis presented similar evidence, reporting an overall prevalence of HPV DNA of 34.5%, with rates of 38.1% in OSCC and 24.1% in head and neck cancer without specific site designation (Termine et al., 2008). Moreover, another meta-analysis reported comparable findings, indicating that the prevalence of HPV infection in OSCC ranged from 13.4-58.0% (Syrjänen and Syrjänen, 2019).

Within the HPV family, high-risk types 16 and 18 appear to be more commonly found in OSCC and exhibit a stronger association with this form of cancer than low-risk types (Ndiaye et al., 2014). High-risk HPV types were detected 2.8-fold more often than low-risk HPVs in OSCC (Miller and Johnstone, 2001). In all HPV type-specific meta-analyses, type 16 emerged as the most common HPV type detected in OSCC cases (Ndiaye et al., 2014; Shaikh et al., 2015). It is of interest that the detection rate of HPV type 18 in OSCC is higher in certain regions of the world, especially in Asia (Zhuang et al., 2022).

Previous studies conducted on HPV infection in OSCC have indicated a broad spectrum of prevalence of HPV infection, ranging from 0-62.8%, shown in Table 4. Many studies have identified the association between HPV infection and OSCC (Ostwald et al., 2003; Zhang et al., 2004; Llamas-Martínez et al., 2008; Khanna et al., 2009; Majumder et al., 2009; Szarka et al., 2009; Mathew et al., 2011 Saghravanian et al., 2011; Kristoffersen et al., 2012; Sritippho et al., 2016; Chuerduangphui et al., 2017; Phusingha et al., 2017; Kitichotkul et al., 2022), while the others have found HPV infection less than 10% (Khovidhunkit et al., 2008; Bhosale et al., 2016; Pongsapich et al., 2016; Chotipanich et al., 2018; Nopmaneepaisarn et al., 2019; Rungraungrayabkul et al., 2022). Again, the discrepancy of the results may reflect differences of the genetics, ethnics, geography, and sexual behaviors of patients with OSCC. Taking all of these epidemiological findings into account, it is reasonable to conclude that there is a notable correlation between HPV infection and OSCC.

Table 4. HPV-related oral squamous cell carcinoma.

Note: HPV* = HPV-16/18 and/or other types.

HPV INTEGRATION INTO THE HUMAN GENOME

Most investigations about integration of HPV into the host genomes have been performed in cervical cancer. Chronic infections with high-risk HPVs lead to the development of dysplastic cervical neoplasia (CIN grades I–III), which can potentially progress to invasive cancers (zur Hausen, 1996; 2000). Upon entering the human body, HPV exists in two forms: the episomal form, which has not yet integrated into the host’s DNA, and the integrated form, where it has inserted itself into the host’s DNA and undergone integration (Luft et al., 2001). In productive HPV infections, which are histologically characterized as low-grade precancerous lesions (CIN I), HPV genomes remain episomal. However, in some high-grade lesions (CIN II–III) and most cervical cancers, HPV genomes completely integrate into the host cell genome (Luft et al., 2001; Ostör, 1993).

In the course of the HPV infection process, the virus enters the basal layer of the epithelium through microtrauma and infects the keratinocytes (Rautava and Syrjänen, 2012). While HPV exists in its episomal form within these basal epithelial cells, the virus gradually undergoes replication in the upper differentiated epithelial layers. HPV predominantly resides in the stratified epithelial tissues, utilizing the hosts’ tissue renewal mechanism to fulfill its life cycle. After HPV has replicated and expressed its oncoproteins, the virus can persist and integrate into the host genome. Although HPV DNA integration is not a typical phase of its life cycle; once integration occurs, the virus forfeits its full capacity to replicate and transmit to another individual (Molina et al., 2024). The integration of HPV DNA is a complex process, influenced by various factors including both viral elements and cofactors found within the host and the microenvironment of the cervicovaginal region. Smoking is believed to be a significant cofactor in HPV integration (Nakigozi et al., 2024). Other potential cofactors could involve the anaerobic species of cervicovaginal microbiota, estrogen levels, and concurrent infection with HIV (Quan et al., 2019; Fischer et al., 2022; Lien et al., 2022; Molina et al., 2024).

Previous studies on cervical cancer found that HPV integration into the human genome destroys the E2 ORF, preventing E2 protein production (Jeon and Lambert, 1995). Under normal circumstances, the E2 protein inhibits the expression of the E6 and E7 oncogenes. Therefore, disrupting the E2 gene significantly increases E6 and E7 protein levels, contributing to malignant development (Park et al., 1997; Yoshinouchi et al., 1999). Moreover, according to Mainguené et al., ratio of E2/E6 genes and E2 genes deleted fraction were assessed in head and neck squamous cell carcinoma (HNSCC) including 91.2% of oropharyngeal carcinoma, and lowered E2 expression level was observed compared to E6 expression level in the integrated HNSCC (Mainguené et al., 2022).

CONCLUSION

A significant number of previous studies have shown that HPV is detectable in OSCC and OPMDs particularly OL and OLP with variable rate. Presumably, only some HPV-detected OSCC and HPV-detected OPMDs cases would undergo malignancy through host genomic integration, emphasizing that HPV integration into host genomes is a crucial step for oral carcinogenesis. Evidently, upon host genomic integration, the levels of HPV E6/E7 oncoproteins increase partly as a result of E2 gene disruption. Therefore, increased expression of E6/E7 oncoproteins or the disruption of E2 gene in malignant tissues could reflect a successful integration of HPV. However, there are only limited data of HPV integration in OPMDs and OSCC. Further studies on HPV integration in OPMDs and OSCC would illuminate the actual HPV infection in these premalignant and malignant tissues and may stress the importance of HPV vaccination for not only girls but also boys. 

ACKNOWLEDGEMENTS

The authors are grateful to the Research Funding for graduate students and the Faculty Research Grant, Faculty of Dentistry, Chiang Mai University, Thailand for providing financial support.

AUTHOR CONTRIBUTIONS

All authors assisted in the data researching, analyzing, and summarizing. Suthinard Tangthikul and Anak Iamaroon conducted all of the reviewing processes and wrote the manuscript. All authors have read and approved of the final manuscript.

CONFLICT OF INTEREST

The authors declare that they hold no competing interests.

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