The human papillomavirus family and its role in carcinogenesis

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Contents lists available at ScienceDirect

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Review

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The human papillomavirus family and its role in carcinogenesis

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Massimo Tommasino ∗ Infections and Cancer Biology Group, International Agency for Research on Cancer – World Health Organization, 150 Cours Albert-Thomas, 69372 Lyon cedex 08, France

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Keywords: Human papillomavirus Cancer E6 and E7 oncoproteins Viral persistence Cellular transformation

Human papillomaviruses (HPVs) are a family of small double-stranded DNA viruses that have a tropism for the epithelia of the genital and upper respiratory tracts and for the skin. Approximately 150 HPV types have been discovered so far, which are classified into several genera based on their DNA sequence. Approximately 15 high-risk mucosal HPV types are clearly associated with cervical cancer; HPV16 and HPV18 are the most carcinogenic since they are responsible for approximately 50% and 20% of all cervical cancers worldwide, respectively. It is now also clear that these viruses are linked to a subset of other genital cancers, as well as head and neck cancers. Due to their high level of carcinogenic activity, HPV16 and HPV18 are the most studied HPV types so far. Biological studies have highlighted the key roles in cellular transformation of the products of two viral early genes, E6 and E7. Many of the mechanisms of E6 and E7 in subverting the regulation of fundamental cellular events have been fully characterized, contributing not only to our knowledge of how the oncogenic viruses promote cancer development but also to our understanding of basic cell biology. Despite HPV research resulting in extraordinary achievements in the last four decades, significantly improving the screening and prophylaxis of HPV-induced lesions, additional research is necessary to characterize the biology and epidemiology of the vast number of HPV types that have been poorly investigated so far, with a final aim of clarifying their potential roles in other human diseases. © 2013 Published by Elsevier Ltd.

1. Members of the HPV family and their clinical implications Members of the human papillomavirus (HPV) family are doublestranded circular DNA viruses with an icosahedral capsid and an ability to infect epithelial cells of the skin and oral and genital mucosa. More than 150 HPV types have been isolated and fully sequenced. A HPV phylogenetic tree has been designed that groups the different HPV types into genera based on the homologous nucleotide sequence of the major capsid protein, L1 [1,2]. Fig. 1 shows the main genera and their association with human diseases. The alpha genus comprises approximately 30 HPV types that infect the mucosa of the genital and oral tract as well as several benign cutaneous HPV types that are associated with the development of common skin warts. Based on their oncogenic potential, the mucosal (alpha) HPV types are divided into two groups: low-risk (LR) HPVs (e.g. types 6 and 11), which are mainly associated with benign genital warts, and high-risk (HR) HPVs, which are the etiological agents of cervical cancer [3]. In a recent monograph, the

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International Agency for Research on Cancer (IARC) classified 12 different HR HPV types as carcinogenic to humans: types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 [4]. HPV16 and HPV18 are the types most frequently found in cervical cancers worldwide; HPV16 and HPV18 are detected in approximately 50% and 20% of squamous cell carcinoma of the cervix, respectively [5,6]. In contrast, both HR HPV types are equally associated with approximately 35% of cervical adenocarcinoma [7]. It is now well demonstrated that HR HPV types are also involved in a subset of other genital cancers, such as vulvar, vaginal, anal, and penile cancers, as well as head and neck cancers (HNC). Approximately 25% of oropharyngeal carcinomas worldwide are linked to HR HPV infections, while the role of these viruses in HNC, such as cancers of the oral cavity, larynx, and hypopharynx, appears to be considerably less significant [8,9]. Among the HR HPV types, HPV16 is responsible for the majority (86–95%) of HPV-positive oropharyngeal carcinomas [10]. The higher prevalence of HPV16 in HNC compared with cervical cancer may be explained by intrinsic features of the two distinct anatomical sites. In the oropharynx, the immune system is much more active than in the genital tract. Biological and epidemiological studies have shown that HPV16 is clearly more efficient at evading the host immune response than the other HR HPV types [11,12]. Thus, it is likely that HPV16 is more efficient than other HR HPV types in

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Disease (% attributed cases)

HPV16

Cervical squamous cell carcinoma (~50) Cervical adenocarcinoma (~35) Oropharyngeal cancer (~25)

HPV18

Cervical squamous cell carcinoma (~20) Cervical adenocarcinoma (~35)

HPV31, 33, 35, 39, 45, 51, 52, 56, 58, 59

Cervical squamous cell carcinoma (~30)

mucosal low-risk

HPV6, 11

Benign genital lesions Respiratory papillomatosis

HPV13, 32

Oral focal epithelial hyperplasia

HPV2,3, 27, 57

Skin warts

HPV1

Skin warts

HPV5 and 8

First beta HPV types isolated from SSC of EV indiviuals

HPV9, 12, 14, 15, 17, 19-25, 36-38, 47, 49, 75, 76, 80, 92, 93, 96, 98-100, 104, 105, 107, 110, 111, 113, 115, 118, 120, 122, 124, 143, 145, 150- 152, 159

Likely associated with SCC in EV patients as well as immuno -compromised and immuno -competent individuals

Gamma

cutaneous

Beta

Mu

Alpha

mucosal lhigh-risk

HPV type

cutaneous benign

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HPV4, 48, 50, 60, 65, 88, 95, 101, 103, 108, 109, 112, 115, 116, 119, 121, 123, 126-142, 144, 146-149, 153-158, 161-170

Unknown

Fig. 1. Many of the identified HPV types that belong to different genera (i.e. alpha, beta, gamma and mu) of the HPV phylogenetic tree are shown. In addition, the main diseases that have been associated with different HPV types are described in the left panels of the figure.

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establishing a persistent infection in the oropharynx, which is an essential step for the development of a malignant lesion. LR mucosal HPV types 6 and 11 are also responsible for a laryngeal disease often occurring in children, i.e. respiratory papillomatosis. Interestingly, a recent report has described one recurrent respiratory papillomatosis patient who developed a malignant lung lesion that resulted positive for LR HPV11. Viral DNA analysis revealed that the HPV11 genome detected in the lung cancer tissue contained a duplication of a region containing part of L1, the LCR and the entire E6 and E7 genes [13]. These results highlight the potential oncogenicity of mucosal HPV types, however whether they are involved in other human malignancies remains to be proven. The beta genus comprises a large number of cutaneous HPV types that appear to be involved in the development of nonmelanoma skin cancer (NMSC). Forty-three beta HPV types have been isolated so far. Initial evidence for the possible association of beta HPV types with skin cancer came from the isolation of beta HPV5 and HPV8 in the skin of cancer-prone patients suffering from a rare autosomal recessive genetic disorder called epidermodysplasia verruciformis (EV) [4,14,15]. EV patients are highly susceptible to infection with beta HPV types and develop disseminated pityriasis versicolor-like lesions and flat warts [14]. These skin lesions arise early in life and in approximately 30–60% of cases progress to multifocal squamous cell carcinoma (SCC) on sun-exposed areas of the body. With the development of highly specific and sensitive detection methods, it has become clear that beta HPV types are also abundantly present in the skin of normal individuals [16,17]. Epidemiological studies, using anti-HPV antibodies and/or viral DNA as a marker of infection, have provided evidence that non-EV individuals with a history of skin SCC show a higher positivity for beta HPV infections than do controls [18–24]. It has been shown that beta HPV prevalence is higher in the precursor lesion, actinic keratosis, than in SCC, suggesting that the virus may play a role at an early stage of carcinogenesis [25,26]. Accordingly, analysis of NMSC specimens has revealed that viral DNA may be present in a

limited number of cancer cells [26]. This scenario differs from that observed in cervical cancers, where at least one copy of HR mucosal HPV DNA is detected in each malignant cell [27]. Thus, HR mucosal and beta HPV types may act in different ways in promoting cancer development. Ultraviolet (UV) irradiation is the main risk factor for skin cancer [28–30], inducing irreversible DNA mutations. Since it is well demonstrated that beta HPV E6 and E7 oncoproteins inhibit the DNA repair machinery [31–33], it is likely that beta HPV types facilitate the accumulation of UV-mediated DNA damage and are not required at a later stage for the maintenance of the cancer phenotype. In agreement with this scenario, expression of beta HPV38 E6 and E7 in the skin of mice results, upon chronic UV irradiation, in the development of actinic keratosis-like lesions and subsequently SCC, while no skin lesions are observed in wild-type animals exposed to the same treatment [34]. The fact that impairment of the immune system in organtransplant recipients (OTRs) strongly increases the risk of NMSC further supports the role of an infectious agent in skin carcinogenesis [35–38]. Accordingly, beta HPV infection was found to be associated with an increased risk of NMSC in OTRs [39]. Many functional studies using in vitro and in vivo experimental models highlight the oncogenic properties of beta HPV types [33,34,40–49]. The additional genera, gamma, mu, and nu, include HPV types with a skin tropism that appears to be associated with the development of benign cutaneous lesions, and there are no findings that support their possible involvement in carcinogenesis. 2. Genomic organization of HPV and viral gene products The circular, double-stranded DNA genomes of all HPVs are approximately 8000 bp in size. Molecular cloning and sequencing of the papillomaviruses have revealed a genomic organization typical of all members of the HPV family, with 8 or 9 open reading frames (ORFs) found on the same DNA strand. The HPV genome can be divided into three different regions: (i) a coding region containing

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Fig. 2. The double-stranded DNA HPV16 genome is represented by a grey circle annotated with the nucleotide numbers. The positions of the long control region (LCR) and the early genes (E1–7) and late genes (L1 and L2) are also shown. The early and late promoters, P97 and P670, respectively, are indicated by arrows. The main functions and features of the early and late gene products are listed in the table.

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the early genes E1, E2, E4, E5, E6, and E7; (ii) a region containing the late genes encoding the major (L1) and minor (L2) capsid proteins; and (iii) a non-coding region, termed the long control region (LCR), which is localized between ORFs L1 and E6 and contains most of the regulatory elements involved in viral DNA replication and transcription. Fig. 2 shows the genome of HPV16 and the main functions of the products of early and late genes. Despite the highly conserved structure of the genome, HPV types of different genera have some exclusive features. For instance, the beta HPV genome is relatively short compared with that of the mucosal HPV types, ranging from 7.4 kb to 7.7 kb. This is due to the considerably reduced size of the LCR, about 400 bp compared with 650–900 bp in other HPVs. Beta HPV types also display some differences in the coding region. Most of them lack the E5 gene; the only exception is HPV14. In addition, the E2 ORF of all the beta HPV types is much longer compared with the other HPVs. Also, the HR mucosal HPV types present some specific characteristics. HPV16, HPV18, and HPV31 produce an additional early protein, E8Eˆ 2C, that represses the expression of the viral oncogenes E6 and E7 and, consequently, cellular proliferation [50]. Similarly to the beta HPV genus, gamma HPV types lack the E5 gene. The isolation of three novel and related gamma HPV types (101, 103, and 108) from cervical specimens has recently been reported. Interestingly, the genomes of these three gamma HPV types lack the E6 ORF [51,52]. It is not yet clear whether the life cycles of these viruses differ from those of the other HPV types and do not require the normal functions of E6. Alternatively, it is also possible that E7 or other early proteins from these HPV types have additional properties that compensate for the lack of E6.

copies per cell. Immediately after this, the expression of late genes starts. Finally, viral particles are produced and released. In contrast to mucosal HPV types, nothing is known about the life cycle of the majority of HPV types that belong to the beta and gamma genera. Studies of mucosal HPV types have shown that the first step in HPV infection is the interaction of the viral capsid with the cytoplasmic membrane of cells at the basal layer of the epithelium. This event is mainly mediated by the major capsid protein, L1, which interacts with the cell surface via heparan sulfonated proteoglycan (HSPG) [54,55]. It is also possible that the viral particles bind to another component of the cellular membrane. In fact, it has been proposed that integrin ␣6 may act as a secondary cellular receptor for HPV particles [56]. However, other studies have shown that cells that do not express integrin ␣6 can still be infected by animal or human papillomavirus [54,57]. After binding of HPV16 particles to the cellular membrane, their internalization is mediated by a clathrin-dependent endocytic pathway [58]. Additional findings indicate that other mucosal HPV types may use different endocytosis pathways [59]. It is also highly likely that the minor capsid protein, L2, plays a role in membrane binding and cellular internalization. In fact, anti-L2 antibodies against specific linear epitopes are able to block the internalization of L1/L2 virus-like particles in in vitro assays [60,61]. It has recently been shown that the annexin A2 heterotetramer contributes to HPV16 infection in an L2-dependent manner [62]. Surviladze and colleagues have recently presented evidence of a novel mechanism of viral entry. They observed that after binding to the cell surface, HPV16 particles are released as a soluble complex with HSPGs and growth factors. The growth factors mediate the interaction of the soluble complex with their cognate receptors, facilitating the internalization of the viral particles [63].

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3. HPV infection and life cycle Due to the clear association of HR mucosal HPV types with human carcinogenesis [3], most of the biological studies so far have been focused on these types. HPV infects cells of the basal layer, where it is present at a relatively low copy number. The HR HPV life cycle is tightly linked to the differentiation programme of stratified epithelia (reviewed in [53]). When cells leave the basal layer of the epithelium, HPV initiates the productive phase of its life cycle that is characterized by vegetative viral DNA replication. During this phase, the HPV genome is amplified to more than 1000

4. Natural history of HPV infections The mucosal HPV types are sexually transmitted, and in the female genital tract the area adjacent to the border of the endocervix and ectocervix, known as the transformation zone or squamocolumnar junction, appears to be the preferential site for infection. Approximately 80% of sexually active women get a HPV infection during their lifetime. In most cases, the HPV infections remain asymptomatic and are cleared by the immune system

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Fig. 3. The schematic structure of HPV16 E6 and E7 is shown, with the position of several amino acid motifs that are important for their structure and functions. Both oncoproteins contain CXXC motifs (two in E7 and four in E6) that are able to form zinc complexes. In addition, E6 has a consensus PDZ-binding motif (ETQL) at the C terminus. E7 includes three regions that are homologous to adenovirus E1A (conserved regions 1–3, CR1–3). CR2 comprises the pRb-binding motif (LXCXE) and two serines (31 and 32) that are phosphorylated by casein kinase II (CKII).

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in a relatively short time (6–12 months). In a small number of cases, however infection may persist, and after a period of latency, low- and/or high-grade cervical intraepithelial neoplasia develops, which may later regress, or progress to an invasive cervical carcinoma [64]. Impairment of immune surveillance strongly facilitates viral persistence and, subsequently, HPV-induced carcinogenesis. Studies of immunocompromised patients, such as OTRs or HIVpositive individuals, have shown an increased prevalence of single or multiple HPV infections and associated lesions, compared with healthy people. This confirms that the immune response, mostly T cell-mediated, is directly involved in the clearance of HPVmediated diseases [65,66]. Accordingly, the incidence of cervical cancers and other genital cancers related to HPV is significantly increased in immune-compromised individuals compared with the normal population [67,68]. In addition, smoking, sexual habits, parity, oral contraceptives, and genetic factors have been associated with an increased risk of progression of HPV-mediated disease [69–72].

transgenic mice co-expressing both viral genes under the control of keratinocyte-specific promoters exhibit epidermal hyperplasia and are susceptible to cancer development promoted by various means, e.g. chemical carcinogens or oestrogen treatment (reviewed in [15]). As explained in detail below, E6 and E7 deregulate fundamental cellular events, such as cell cycle, apoptosis, DNA repair, senescence, and differentiation, facilitating the accumulation of DNA damage and the progression towards malignancy. If the HPVinfected cells are rapidly eliminated by the immune system, despite the transforming properties of E6 and E7, they do not have sufficient time to accumulate chromosomal abnormalities and acquire a malignant phenotype. In this scenario, it is clear that the establishment of a chronic infection is a condition sine qua non for the development of HPV-associated malignant diseases. Although it is clear that HR HPV E6 and E7 target cellular pathways related to innate and adaptive immunity, host and environmental factors significantly contribute to the chronicity of HPV infection.

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5. HR HPV E6 and E7 and cancer E6 and E7 from HR HPVs play a key role in carcinogenesis by altering pathways related to the immune response and cellular transformation. Since HPV16 and HPV18 are the most frequently detected types in cervical cancer worldwide, their E6 and E7 proteins have been extensively studied. They lack enzymatic activities and exert their functions by associating with a broad spectrum of cellular proteins (for review, see [73–76]). Due to space limitations, this review will focus on E6 and E7 mechanisms involved in cellular transformation. It is recommended that readers refer to recent reviews of HPV mechanisms responsible for the deregulation of immune-response-related pathways (reviewed in [65,77]). The first indication of the oncogenic properties of E6 and E7 was provided by studies on cervical cancer-derived cells, e.g. SiHa and CaSki cells [78]. In these cell lines, viral DNA was found to be randomly integrated in the host genome, leading to the disruption of several viral genes and preservation of E6 and E7, which were actively transcribed. Many studies have shown that the frequency of viral DNA integration increases with the severity of the cervical lesion, indicating that this event is implicated in the progression of the disease [79]. Continuous E6 and E7 expression is necessary for the maintenance of the malignant phenotype. Silencing of both viral genes in cervical cancer-derived cell lines results in rapid cellular death [80]. The key role of E6 and E7 oncoproteins in HPV-mediated carcinogenesis is further highlighted by studies that demonstrate the ability of E6 and E7 to induce transformation of immortalized rodent fibroblasts, e.g. NIH 3T3, and to immortalize primary human keratinocytes [81]. In agreement with the in vitro assays,

6. Transforming properties of E6 E6 is a basic and cysteine-rich protein of approximately 150 amino acids. The major structural characteristic of E6 is the presence of two zinc-binding regions, referred to as E6N and E6C. Both domains contain two cysteine motifs (CXXC), which are conserved in the E6 proteins of all HPV types (Fig. 3). The structures of isolated E6N and E6C, as well as of the entire E6 protein, have been determined [82–84]. These structural studies highlight features of E6 that are in agreement with its ability to associate with a vast number of cellular proteins (reviewed in [85,86]). One of the most characterized properties of HR HPV16 E6 is its ability to induce degradation of the tumour suppressor protein p53 via the ubiquitin pathway (Fig. 4). p53 is a transcription factor that regulates the expression of genes encoding regulators of cell cycle, DNA repair machinery, and apoptosis. Under cellular stress, such as hypoxia or DNA damage, p53 triggers cell cycle arrest or apoptosis to guarantee the integrity of the cellular genome. By blocking the cell cycle, p53 prevents the replication of damaged DNA and allows the cell to repair damage before S phase. Alternatively, if DNA damage is too great and difficult to repair, p53 can divert the cell into apoptosis, thus preventing the production of potentially transformed progeny. HPV16 E6 binds to the conserved LXXLL motif of a 100 kDa cellular protein, termed E6-associated protein (E6AP), which functions as an E3 ubiquitin protein ligase. The E6/E6AP complex then binds to the central region (also termed the core domain) of p53, which becomes rapidly ubiquitinated and targeted to proteasomes [87–89].

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Fig. 4. Many of the properties of E6 and E7 from different HPV types and their induced events are shown. The dark grey boxes describe the events induced by the different E6 oncoproteins, while the light grey boxes describe the ones mediated by the E7 oncoproteins.

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E6 from HR HPV types and, to a lesser extent, LR HPV types, is also able to inhibit the expression of p53-regulated genes by directly interacting with the transcriptional co-activators CBP and p300 [90]. E6 from beta HPV5, HPV8, and HPV38 also binds to p300 [33,44]. In the case of HPV38 E6, the interaction with p300 results in the prevention of p53 acetylation and inhibition of its transcriptional activities [44], while HPV8 E6 promotes p300 degradation [33], which strongly decreases the levels of ATR protein, a key player in UV-induced damage signalling (Fig. 4). As a consequence, HPV8 E6-expressing cells, when exposed to UV irradiation, accumulate more thymine dimer mutations compared with mock cells [33]. One of the UV-induced responses is p53 phosphorylation and stabilization. Beta HPV23 E6 is able to prevent p53 phosphorylation at serine 46 upon UV irradiation, by interacting with and inhibiting the kinase activity of HIPK2 [45]. Besides the involvement in p53 degradation, E6/E6AP interaction is involved in other HPV-induced events, e.g. the transcriptional activation of the hTERT (human telomerase reverse transcriptase) gene, which encodes the catalytic subunit of the telomerase complex [91]. Somatic cells are characterized by very little or no telomerase activity, and telomeres shorten as a function of cellular division to finally reach a critical size, leading to replicative senescence (reviewed in [92]). In contrast, HPV16-infected cells display a very high level of telomerase activity, allowing telomere length maintenance and indefinite proliferation. HPV16 E6 is able, through its association with E6AP, to promote the degradation of the transcriptional repressor NFX1-91, and consequently to activate hTERT transcription [93] (Fig. 4). Silencing of E6AP expression by small interfering RNAs abolishes the transcriptional activation of hTERT mediated by HPV16 or HPV18 E6 [94]. Recent findings indicate that NFX1-91 negatively regulates the transcription of p105, which is part of the non-canonical NF-␬B pathway. Thus, E6mediated degradation of p105 leads to stimulation of the NF-␬B signalling pathway [95,96]. It appears that HR mucosal HPV types use more than one mechanism to activate hTERT transcription. It has been shown that HPV16 E6, via direct binding, increases Myc efficiency in activating the

hTERT promoter [97]. It is likely that this HPV-mediated hTERT transcriptional activation is not dependent on E6/E6AP interaction. In agreement with this model, it has recently been shown that HPV16 E6 mutants deficient for E6AP binding are still able to stimulate the expression of hTERT [98]. The E6 protein of beta HPV types is also able to activate hTERT in an E6AP-dependent mechanism. Bedard and colleagues have performed a comparative study on E6 from beta HPV types 5, 20, 22, and 38 and showed that HPV38 E6 significantly stimulated telomerase activity, although at a lower level than HPV16 E6. In contrast, E6 from other beta HPVs had a much reduced activity [99]. Interestingly, the efficiency of beta HPV E6 in activating telomerase activity correlated with the relative strength of the interaction between E6 and E6AP or NFX1-91. Accordingly, HPV38 E6, together with E7, efficiently immortalized human keratinocytes [41,42]. Despite the ability to bind E6AP, beta HPV38 E6 does not induce p53 degradation [37]. However, a recent study showed that E6 from at least one of the beta HPV types, HPV49, has the same ability as HPV16 E6 to degrade p53 in an E6AP-dependent mechanism [100] (Fig. 4). E6 from LR and HR mucosal HPV types, as well as E6 from beta and other cutaneous HPV types, has developed an additional mechanism to inhibit the apoptotic response via the induction of degradation of Bak, a member of the Bcl-2 family [101–103]. This activity is also mediated by the interaction with E6AP and the ubiquitin–proteasome pathway. In the skin, Bak is highly stabilized and activated throughout the entire epidermis in response to UV irradiation. Thus, in the context of cutaneous HPV infection, Bak degradation may be required to antagonize the anti-proliferative effects of UV irradiation (Fig. 4). Members of the membrane-associated guanylate kinase (MAGUK) family are additional targets of the HR HPV E6 [76]. These cellular proteins are localized in the cytoplasmic membrane and regulate cell–cell contact and cell polarity. They contain various protein/protein interaction domains, including PDZ motifs. E6 from HR HPV types has a PDZ-binding motif at the C terminus that mediates the interaction with MAGUK family members. E6/MAGUK

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association leads to degradation of the cellular protein, with consequent loss of cell–cell contact and cell polarity. Deletion of the HR HPV E6 PDZ-binding motif significantly affects its transforming properties in in vitro and in vivo experimental models [104,105]. Although the ability to target the cellular PDZ proteins is a property of E6, it has been shown that E7 can be involved in the event. HPV16 E6 associates with and promotes the degradation of the PDZ protein, Na(+)/H(+) exchange regulatory factor 1 (NHERF-1). HPV16 E7, through its ability to activate the cyclin-dependent kinase complexes, promotes the accumulation of the phosphorylated form of NHERF-1, which is more efficiently targeted by E6 (Fig. 4). It is worth mentioning that E6 proteins from LR mucosal HPV and beta HPV types do not contain the PDZ-binding site at the C terminus, highlighting the functional differences in the HPV family. In addition to what has been described above, a large number of E6 targets have been identified (for review, see [73–76,106]). However, in several cases the biological significance of these interactions is not yet entirely understood.

7. Transforming properties of E7 E7 is an acidic phosphoprotein of approximately 100 amino acids that, similarly to E6, contains zinc-binding motifs. E7 is structurally and functionally related to adenovirus E1A and, based on this similarity, is divided into three domains: conserved regions 1–3 (CR1–3) (Fig. 3). CR2 of several E7 proteins includes a phosphorylation site for casein kinase II. The same region also contains an LXCXE motif that mediates the interaction with the tumour suppressor gene product retinoblastoma (pRb1) and its related proteins, p107 and p130. All three cellular proteins are intimately linked to cell cycle control. pRb1 negatively regulates, via direct association, the activity of members of the E2F family (E2F1–3), maintaining the cell in a quiescent state during the G0/G1 phase of the cell cycle. The association of HR HPV E7 with pRb leads to degradation of pRb via proteasomal pathways, with consequent activation of E2Fregulated transcription. The genes regulated by E2F1–3 include cyclin A and cyclin E, which are positive regulatory subunits of cyclin-dependent kinase (CDK) complexes. Accumulation of cyclins results in activation of CDKs and cell cycle progression (Fig. 4). HPV16 E7 induces pRb degradation by associating with a cullin 2-containing complex [107]. However, it is not known whether E7 from other HPV types promotes pRb degradation using similar mechanisms. In rodent fibroblasts, E7 from beta HPV38 and other HPV types also degrades pRb, while in human keratinocytes the viral oncoprotein inhibits pRb function by inducing its phosphorylation [100]. The other two pRb-related proteins, p107 and p130, are part of co-repressor complexes containing other members of the E2F family (E2F4, E2F4, or E2F5) and histone deacetylase enzymes [108,109]. These complexes bind to specific E2F elements, resulting in inhibition of gene expression. It has been shown that HPV16 E7 destabilizes p130 [110], most likely altering the inhibitory functions of the E2F complexes. Three additional members of the E2F family, E2F6–8, have been identified [109]. They lack a transactivation domain and act as repressors of transcription in a manner that is independent of pRb, p107, or p130. E2F6 interacts with several polycomb complexes, leading to epigenetic changes associated with gene silencing, e.g. histone 3 lysine 27 trimethylation (H3K27me3) [111,112]. HPV16 E7 interacts with E2F6, interfering with the inhibitory function of E2F6 in cellular gene expression [113]. Besides its ability to target E2F complexes, E7 deregulates the cell cycle via direct binding of the CDK inhibitors p21WAF1/CIP1 and p27KIP1, causing neutralization of their inhibitory effects on the cell cycle [114–116]. In addition, HPV16 E7 can directly interact with cyclin A/CDK2 complexes [117]. A more recent study has

shown that the viral protein strongly stimulates the histone H1 kinase activity of CDK2 in complex with either cyclin A or cyclin E. In the same study, cross-linking experiments have shown that the interaction of HPV16 E7 with CDK complexes is mainly mediated by the cyclin subunits [118]. In contrast to mucosal HPV E7, the biological properties of E7 from beta HPV types have not been well characterized. Recent studies have shown that beta HPV38 E7 not only is involved in the deregulation of the cell cycle via inactivation of pRb, but also is able to alter the expression of p53-regulated genes [40,119,120] (Fig. 4). Expression of HPV38 E6 and E7 in human keratinocytes induces accumulation of a potent antagonist of p53/p73-regulated pathways, Np73␣ [40,119]. In particular, beta HPV38 E7 promotes, via an unknown mechanism, nuclear translocation of the I␬B kinase beta (IKK␤) complex, which in turn associates with and phosphorylates Np73␣ leading to its stabilization. Np73␣ and IKK␤ are part of an inhibitory complex, together with two epigenetic enzymes, namely DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2), which are recruited to a subset of p53-regulated promoters [120]. In addition to the rescue of p53 transcriptional functions, down-regulation of Np73␣ RNA levels in HPV38 E6/E7 keratinocytes also results in a downregulation of hTERT expression, supporting the idea that Np73␣ positively regulates hTERT promoter activity [42] (Fig. 4). Thus, beta HPV38 appears to have two independent mechanisms for activation of telomerase activity, mediated by both E6 and E7 oncoproteins. Interestingly, the ability of beta HPV38 to induce Np73␣ accumulation is shared by the oncogenic Epstein–Barr virus [121], underlining the importance of the event in virus-mediated cellular transformation. In conclusion, as described for E6, the E7 oncoprotein is also able to interact with a large number of cellular proteins, only some of which have been described in this review; for further discussions, see other recent reviews [73,75,122]

8. Conclusions The initial hypothesis of the association of cervical cancer with HPV infection was proposed almost 40 years ago [123]. Since then, a large number of biological and epidemiological studies have entirely confirmed the association of HR HPV types with cervical cancer. Biological studies have elucidated in detail many of the molecular mechanisms of E6 and E7 oncoproteins for altering the regulation of fundamental cellular events, such as cell cycle, apoptosis, differentiation, senescence, cell polarity, and activation of immune-response-related pathways. These studies not only are important for understanding the viral mechanisms but also have significantly contributed to the understanding of cell biology. The epidemiological studies have demonstrated the association of HR HPV types with pre-malignant and malignant cervical lesions worldwide, highlighting the worldwide predominance of HPV16 and 18 and different distribution of the other HR HPV types in different geographical areas. Most importantly, these studies have demonstrated that HR HPV infections are also involved in a subset of other genital cancers, i.e. cancers of the vagina, vulva, penis, and anus, as well as cancer of the oropharynx. These research activities have had a great impact on public health, facilitating the establishment of novel screening and prophylactic strategies. The generation of the L1-based prophylactic vaccine has been a remarkable achievement. The vaccine has proven to be highly efficient in preventing HPV infection and the development of pre-malignant cervical lesions. Despite the large effort in HPV research and the achievements attained, many questions remain to be answered. For instance, very

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little is known about the natural history of HR HPV infections in sites other than cervix. Very limited information is available on the natural history of HR HPV infections in the oral cavity and viral molecular mechanisms occurring during carcinogenesis of the oropharynx. In particular, it is not yet clear whether HR HPV cooperates with environmental risk factors in this anatomical region. In addition, the classification of LR mucosal HPV types as benign viruses needs to be further evaluated. Regarding cutaneous HPV types, only a limited number of biological and epidemiological studies have been performed on beta HPV types. No information is available on the biological properties of the gamma HPV types that are highly prevalent on the skin of normal individuals. Although the initial findings support a possible link between beta HPV types and NMSC, the issue is still under debate. In conclusion, it is obvious that much HPV research still remains to be done and many more findings will come in the future, improving our knowledge of cellular biology and virus-mediated carcinogenesis.

Conflict of interest statement The author declares that there is no conflict of interest.

Acknowledgements I apologize to those authors whose important contributions to HPV research could not be cited or adequately discussed due to space limitations. I thank the IARC Director, Dr. Christopher P. Wild, and all members of the Infections and Cancer Biology Group for their constant support, Drs. Karen Muller and Rachel Purcell for the editing and Isabelle Rondy for the preparation of this manuscript. The work performed in the group is partially supported by a grant from the European Commission, HPV-AHEAD (FP7-HEALTH-2011282562). References [1] Bernard HU, Burk RD, Chen Z, van Doorslaer K, zur Hausen H, de Villiers EM. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology 2010;401(1):70–9. [2] de Villiers EM. Cross-roads in the classification of papillomaviruses. Virology 2013;445(1–2):2–10. [3] zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002;2(5):342–50. [4] Bouvard V, Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, et al. A review of human carcinogens—Part B: biological agents. Lancet Oncol 2009;10(4):321–2. [5] Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348(6):518–27. [6] Smith JS, Lindsay L, Hoots B, Keys J, Franceschi S, Winer R, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer 2007;121(3):621–32. [7] Li N, Franceschi S, Howell-Jones R, Snijders PJ, Clifford GM. Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: variation by geographical region, histological type and year of publication. Int J Cancer 2011;128(4):927–35. [8] Marur S, D’Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol 2010;11(8):781–9. [9] Halec G, Holzinger D, Schmitt M, Flechtenmacher C, Dyckhoff G, Lloveras B, et al. Biological evidence for a causal role of HPV16 in a small fraction of laryngeal squamous cell carcinoma. Br J Cancer 2013;109(1):172–83. [10] Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005;14(2):467–75. [11] Hasan UA, Bates E, Takeshita F, Biliato A, Accardi R, Bouvard V, et al. TLR9 expression and function is abolished by the cervical cancer-associated human papillomavirus type 16. J Immunol 2007;178(5):3186–97. [12] Schiffman M, Herrero R, Desalle R, Hildesheim A, Wacholder S, Rodriguez AC, et al. The carcinogenicity of human papillomavirus types reflects viral evolution. Virology 2005;337(1):76–84.

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