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Cited by 138Cervical Cancer and HPV ResearchCancer-related Molecular PathwaysViral-associated cancers and disorders

The DOI matches its Crossref record; 375 of the 392 references it cites were found in a registry or an index; none of the 411 sources its claims cite is checked for support yet.

The Not-So-Good, the Bad and the Ugly: HPV E5, E6 and E7 Oncoproteins in the Orchestration of Carcinogenesis

Open access
Basukala, Om, Banks, Lawrence·2021·Viruses
DOI 10.3390/v13101892PMC PMC8541208
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Abstract

Infection with HPV starts with the access of the viral particles to basal cells in the epidermis, potentially via microtraumas to the skin. The basal cells are able to keep away these pathogens in normal circumstances through a robust immune response from the host, as HPV infections are, in general, cleared within 2 to 3 weeks. However, the rare instances of persistent infection and/or in cases where the host immune system is compromised are major risk factors for the development of lesions potentially leading to malignancy. Evolutionarily, obligatory pathogens such as HPVs would not be expected to risk exposing the host to lethal cancer, as this would entail challenging their own life cycle, but infection with these viruses is highly correlated with cancer and malignancy—as in cancer of the cervix, which is almost always associated with these viruses. Despite this key associative cause and the availability of very effective vaccines against these viruses, therapeutic interventions against HPV-induced cancers are still a challenge, indicating the need for focused translational research. In this review, we will consider the key roles that the viral proteins play in driving the host cells to carcinogenesis, mainly focusing on events orchestrated by early proteins E5, E6 and E7—the not-so-good, the bad and the ugly—and discuss and summarize the major events that lead to these viruses mechanistically corrupting cellular homeostasis, giving rise to cancer and malignancy.

Overview

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TL;DR

This review argues that HPV E5, E6, and E7 oncoproteins collectively rewire host cellular homeostasis to drive carcinogenesis, with E6/E7 inactivating p53/pRB and E5 contributing to proliferation, apoptosis resistance, and immune evasion. It synthesizes mechanisms across cancer hallmarks and notes that therapeutic agents against HPV-mediated cancers remain lacking.

Key findings

  • HPV infection is usually cleared: 70–90% of infections are asymptomatic and resolved within 1–2 years, but 5–10% of infected individuals develop persistent infection that can lead to malignancy; >70% of HPV-mediated cancers are caused by high-risk types 16 and 18.
  • Viral integration disrupts E2 repression and drives high E6/E7 expression; HPV-18 genome is integrated in 100% of HPV-18-positive cancers, while HPV-16 can remain episomal in up to 25% of cancers.
  • E6 and E7 inactivate tumor suppressors: E7 binds pRB via LXCXE and destabilizes pocket proteins, while E6 forms an E6–E6AP complex to ubiquitinate and degrade p53; low-risk E7 binds pRB approximately 10-fold less efficiently and cannot target all pRB family proteins.
  • E5 contributes via EGFR/MAPK signaling, apoptosis resistance, and immune evasion, including downregulation of MHC class I/II and CD1d; in HNSCC, E5-expressing tumors were resistant to anti-PD-1/PD-L1 immunotherapy, and rimantadine improved checkpoint blockade response.

Methods

  • Narrative review; no primary experimental data or systematic search described.
  • Synthesizes published literature on HPV E5, E6, and E7, organized around cancer hallmarks such as evading growth suppressors, resisting cell death, sustaining proliferation, replicative immortality, invasion/metastasis, angiogenesis, metabolism, genome instability, immune evasion, and inflammation.
  • Main analysis is thematic/mechanistic synthesis of cited studies.

Limitations

  • Stated: many mechanisms behind the carcinogenic effects of these viral oncoproteins remain uncovered, and specific therapeutic agents against HPV-mediated cancer have not yet been found; how detected somatic mutations contribute to HPV-mediated carcinogenesis is not fully understood.
  • Evident: as a narrative review, it does not perform systematic literature retrieval, quality appraisal, or quantitative meta-analysis, so conclusions depend on selected cited studies.

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Integrity signals

Registry

Crossref · 10.3390/v13101892

Cites

375 of 375 references verified0 citation errors · 0 not checkable

Statistics

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Figures

Figure 1 The hallmarks of cancer adapted from Hanahan and Weinberg 2016 [2]. A schematic illustrating eight distinct functional capabilities and two facilitators that are necessary conditions for the manifestation of malignant disease—cancer—and the expression of the HPV oncoproteins responsible for attaining these functions.
Figure 1 The hallmarks of cancer adapted from Hanahan and Weinberg 2016 [2]. A schematic illustrating eight distinct functional capabilities and two facilitators that are necessary conditions for the manifestation of malignant disease—cancer—and the expression of the HPV oncoproteins responsible for attaining these functions.CC BY · PubMed Central
Figure 2 From infection to the development of cancer and malignancy, mediated by HPV (adapted and modified from References [22,23]. (A) Infection with HPV is normally cleared with 1 to 2 weeks; however, in certain individuals, persistent infection and a lack of immune clearance can lead to deregulation of the viral life cycle and viral genome integration, making them major risk factors for tumour development and progression towards cancer and malignancy. The progression towards invasive cancer and metastasis involves several changes, including chromosomal abnormalities, epigenetic modifications, genome instability and accumulating mutations and tumour-promoting inflammation, taking 2 to 20-plus years. (B) A cartoon representing infection by HPVs and progression to cancer. Infection with HPV is thought to occur via microtraumas in the epithelium, allowing access of the virus to the basal cell layer. HPV maintains its genome in the basal cells, and, as these cell divide, there is coordinated expression of early viral proteins, including E6 and E7, that allows the differentiation-determined cells to reinitiate the cell cycle. As these cells reach the upper squamous layers, with a concomitant expression of viral late gene products L1 and L2, new virions are released upon desquamation. Various regions of the cervix composed of stratified epithelium of the ectocervix, the transformation zone and the columnar epithelium of the cervix and endocervix are indicated in the cartoon, suggesting major sites of productive infections leading to the release of viral particles and abortive infection associated with deregulated HPV gene expression, potentially leading to squamous cell carcinoma and adenocarcinoma.
Figure 2 From infection to the development of cancer and malignancy, mediated by HPV (adapted and modified from References [22,23]. (A) Infection with HPV is normally cleared with 1 to 2 weeks; however, in certain individuals, persistent infection and a lack of immune clearance can lead to deregulation of the viral life cycle and viral genome integration, making them major risk factors for tumour development and progression towards cancer and malignancy. The progression towards invasive cancer and metastasis involves several changes, including chromosomal abnormalities, epigenetic modifications, genome instability and accumulating mutations and tumour-promoting inflammation, taking 2 to 20-plus years. (B) A cartoon representing infection by HPVs and progression to cancer. Infection with HPV is thought to occur via microtraumas in the epithelium, allowing access of the virus to the basal cell layer. HPV maintains its genome in the basal cells, and, as these cell divide, there is coordinated expression of early viral proteins, including E6 and E7, that allows the differentiation-determined cells to reinitiate the cell cycle. As these cells reach the upper squamous layers, with a concomitant expression of viral late gene products L1 and L2, new virions are released upon desquamation. Various regions of the cervix composed of stratified epithelium of the ectocervix, the transformation zone and the columnar epithelium of the cervix and endocervix are indicated in the cartoon, suggesting major sites of productive infections leading to the release of viral particles and abortive infection associated with deregulated HPV gene expression, potentially leading to squamous cell carcinoma and adenocarcinoma.CC BY · PubMed Central
Figure 3 Schematic representation of HPV oncoproteins E5, E6 and E7. HPV16-E5 is an 83-amino acid-long transmembrane protein with three transmembrane domains (TMDI-III). HPV-16 E6 is an 158 amino acid protein with two CXXC (Cys-X-X-Cys,) motifs, which participate in coordinating with zinc ions and are indicated in the schematic. The C-terminus PDZ-binding motif (PBM) sequence ‘ETQV’ is shown, which can be phosphorylated by AKT, Chk2 via PKA and Chk1 kinases. HPV-16 E7 is a cytoplasmic phosphoprotein. The position of the conserved regions (CR1, CR2 and CR3) and CXXC (Cys-X-X-Cys) motifs, which participate in coordinating zinc ions, are also indicated. The LXCXE motif and CKII phosphorylation site in the CR2 region are important for targeting the pRB and related pocket proteins.
Figure 3 Schematic representation of HPV oncoproteins E5, E6 and E7. HPV16-E5 is an 83-amino acid-long transmembrane protein with three transmembrane domains (TMDI-III). HPV-16 E6 is an 158 amino acid protein with two CXXC (Cys-X-X-Cys,) motifs, which participate in coordinating with zinc ions and are indicated in the schematic. The C-terminus PDZ-binding motif (PBM) sequence ‘ETQV’ is shown, which can be phosphorylated by AKT, Chk2 via PKA and Chk1 kinases. HPV-16 E7 is a cytoplasmic phosphoprotein. The position of the conserved regions (CR1, CR2 and CR3) and CXXC (Cys-X-X-Cys) motifs, which participate in coordinating zinc ions, are also indicated. The LXCXE motif and CKII phosphorylation site in the CR2 region are important for targeting the pRB and related pocket proteins.CC BY · PubMed Central
Figure 4 Evading growth suppressors. Unlike normal cells, where the growth and proliferation are tightly controlled, cells expressing HPV oncoproteins act to evade the key tumour suppressors pRB and p53. HPV-E7 can associate with pRB and inactivate the repressive function of the pRB/E2F transcription complex, leading to the expression of S-phase genes (cell cycle regulators, including cdc25a, cyclin E and A and replication enzymes and others) in otherwise cell cycle-exited and differentiating keratinocytes, leading to re-entry to the S phase. Further, high-risk E7 can downregulate pRB via proteasomal degradation via the cullin-2 ubiquitin ligase complex. HPV-16 E7 associates with cdk inhibitors p21Cip1 and p27Kip1, abrogates the inhibition of cdk2 activity and enhances the transcriptional activation of cdc25a, leading to the dephosphorylation of inhibitory phosphorylation in cdk-2/cyclin E/A. This leads to activation of the p53 tumour suppressor; however, high-risk E6 can inactivate and degrade p53 via the ubiquitin proteasome pathway involving the E6AP ubiquitin ligase complex. ub—ubiquitin and pp—2-25 residue peptides.
Figure 4 Evading growth suppressors. Unlike normal cells, where the growth and proliferation are tightly controlled, cells expressing HPV oncoproteins act to evade the key tumour suppressors pRB and p53. HPV-E7 can associate with pRB and inactivate the repressive function of the pRB/E2F transcription complex, leading to the expression of S-phase genes (cell cycle regulators, including cdc25a, cyclin E and A and replication enzymes and others) in otherwise cell cycle-exited and differentiating keratinocytes, leading to re-entry to the S phase. Further, high-risk E7 can downregulate pRB via proteasomal degradation via the cullin-2 ubiquitin ligase complex. HPV-16 E7 associates with cdk inhibitors p21Cip1 and p27Kip1, abrogates the inhibition of cdk2 activity and enhances the transcriptional activation of cdc25a, leading to the dephosphorylation of inhibitory phosphorylation in cdk-2/cyclin E/A. This leads to activation of the p53 tumour suppressor; however, high-risk E6 can inactivate and degrade p53 via the ubiquitin proteasome pathway involving the E6AP ubiquitin ligase complex. ub—ubiquitin and pp—2-25 residue peptides.CC BY · PubMed Central
Figure 5 Resisting cell death. One of the major roles played by HPV oncoproteins in resisting cell death is evading apoptosis. Both extrinsic and intrinsic apoptotic pathways are deregulated to attain this function by HPV-E5, -E6 and -E7. The extrinsic apoptotic pathway is activated upon receptor trimerization and the subsequent recruitment of adaptor molecules and procaspase 8 to the DISC. The activation of caspase 8 then leads to the activation of downstream executioner caspases 3 and 7, leading to cell death/apoptosis. The intrinsic apoptotic pathway is activated by external stimuli (UV-radiation, oxidative stress, DNA damage, starvation, etc.), leading to the formation of pores in the mitochondrial membrane and release of mitochondrial inner membrane proteins (cytochrome c, SMAC) into the cytosol. Released cytochrome c and pro-caspase 9 form the apoptosome, leading to activating caspase 9, which, in turn, activates downstream executioner caspases 3 and 7, leading to apoptosis. E5 can downregulate the Fas receptor and perturb the formation of the DISC complex, thus abrogating the extrinsic apoptotic pathway. Further, E5 can perturb ROS-induced Bax activation and inhibit the apoptotic response to UV B radiation. E6 can block extrinsic pathways by binding the death domain, leading to its proteasomal degradation. E6 inactivates p53, Bax and Bak, thus abrogating MOMP and the release of cytochrome c and, thus, inhibiting the intrinsic apoptotic pathway. E6 can also inhibit antiapoptotic c-IAP2, blocking the formation of the apoptosome and activation of the executioner caspases. E7 seems to have a dual function in activating and abrogating apoptosis; however, E7 has been demonstrated to perturb TNF receptor-induced apoptosis by upregulating c-IAP2 and suppressing caspase 8. FADD—Fas-associated protein with death domain, TNF—tumour necrosis factor, TRAIL—FasL and TNF-related apoptosis-inducing ligand, TRAF2—TNF receptor-associated factor 2, DISC—death-induced signalling complex, c-IAP2—cellular inhibitor of apoptosis protein 2, RIP—receptor interacting protein and MOMP—mitochondrial outer membrane permeabilization.
Figure 5 Resisting cell death. One of the major roles played by HPV oncoproteins in resisting cell death is evading apoptosis. Both extrinsic and intrinsic apoptotic pathways are deregulated to attain this function by HPV-E5, -E6 and -E7. The extrinsic apoptotic pathway is activated upon receptor trimerization and the subsequent recruitment of adaptor molecules and procaspase 8 to the DISC. The activation of caspase 8 then leads to the activation of downstream executioner caspases 3 and 7, leading to cell death/apoptosis. The intrinsic apoptotic pathway is activated by external stimuli (UV-radiation, oxidative stress, DNA damage, starvation, etc.), leading to the formation of pores in the mitochondrial membrane and release of mitochondrial inner membrane proteins (cytochrome c, SMAC) into the cytosol. Released cytochrome c and pro-caspase 9 form the apoptosome, leading to activating caspase 9, which, in turn, activates downstream executioner caspases 3 and 7, leading to apoptosis. E5 can downregulate the Fas receptor and perturb the formation of the DISC complex, thus abrogating the extrinsic apoptotic pathway. Further, E5 can perturb ROS-induced Bax activation and inhibit the apoptotic response to UV B radiation. E6 can block extrinsic pathways by binding the death domain, leading to its proteasomal degradation. E6 inactivates p53, Bax and Bak, thus abrogating MOMP and the release of cytochrome c and, thus, inhibiting the intrinsic apoptotic pathway. E6 can also inhibit antiapoptotic c-IAP2, blocking the formation of the apoptosome and activation of the executioner caspases. E7 seems to have a dual function in activating and abrogating apoptosis; however, E7 has been demonstrated to perturb TNF receptor-induced apoptosis by upregulating c-IAP2 and suppressing caspase 8. FADD—Fas-associated protein with death domain, TNF—tumour necrosis factor, TRAIL—FasL and TNF-related apoptosis-inducing ligand, TRAF2—TNF receptor-associated factor 2, DISC—death-induced signalling complex, c-IAP2—cellular inhibitor of apoptosis protein 2, RIP—receptor interacting protein and MOMP—mitochondrial outer membrane permeabilization.CC BY · PubMed Central

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Metadata

Authors
Basukala, O., & Banks, L.
Affiliations
International Centre for Genetic Engineering and Biotechnology (IT)
Corresponding author
Banks, Lawrence
ORCID
Venue
Viruses
Publisher
MDPI AG
Published
2021-09-22
Volume
13
Issue
10
Pages
1892
ISSN
1999-4915 (ISSN-L)
DOI
10.3390/v13101892
PMC
PMC8541208
OpenAlex
W3200328701
Cited by
137
References
392
Citations by year
2026: 25 · 2025: 35 · 2024: 34 · 2023: 22 · 2022: 20 · 2021: 1
FWCI
3.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Viruses (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Associazione Italiana per la Ricerca sul Cancro (IG2019 - ID. 23572)
Topics
  • Health Sciences › Medicine › Epidemiology › Cervical Cancer and HPV Research
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
Keywords
human papillomavirus, E6 oncoprotein, E7 oncoprotein, viral oncogenesis, carcinogenesis, persistent HPV infection, cervical cancer, basal keratinocytes, host immune response, cellular homeostasis, HPV vaccine, therapeutic interventions
MeSH terms
Persistent Infection, Animals, Female, Humans, Oncogene Proteins, Viral, Papillomaviridae, Papillomavirus Infections, Mice, Carcinogenesis

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