Expression of HPV16 E5 down-modulates the TGFbeta signaling pathway

French, Deborah; Belleudi, Francesca; Mauro, Maria Vittoria; Mazzetta, Francesca; Raffa, Salvatore; Fabiano, Vincenza; Frega, A; Torrisi, Maria Rosaria

doi:10.1186/1476-4598-12-38

Cited by 48 publications

(52 citation statements)

References 24 publications

(31 reference statements)

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“…24 These data were confirmed in other studies utilizing RT real time PCR on mRNA from LSILs and HSILs, respectively. [25][26] However, all HPV16 transcripts are polycistronic and the resulting early primary transcripts have 3 exons and 2 introns, which undergo alternative RNA splicing.…”

Section: Discussionmentioning

confidence: 99%

HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

Paolini¹,

Curzio²,

Cordeiro

et al. 2016

Human Vaccines & Immunotherapeutics

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HPV16 persistent infection is a well-known condition that precedes human cancer development. High risk HPV E5 proteins cooperate with E6/E7 oncogenes to promote hyper-proliferation of infected cells leading to possible cancer progression. Thus, presence of E5 viral transcripts could be a key marker of active infection and, in turn, a target of immunotherapy. Purpose of the study is to detect E5 transcripts in clinical samples and to explore the activity of novel anti-HPV16 E5 DNA vaccines. HPV transcripts were detected by PCR with specific primers encompassing the splice-donor sites of E5 transcript. For E5-based immunotherapies, 2 E5-based versions of DNA vaccines carrying whole E5 gene or a synthetic multiepitope gene were improved by fusion to sequence of PVX coat protein. These vaccines were challenged with a new luminescent animal model based on C3-Luc cell line. E5 transcripts were detected in clinical samples of women with HPV positive low-grade SIL, demonstrating the validity of our test. In C3 pre-clinical mouse model, vaccine candidates were able to induce a strong cellular immunity as indicated by ELISPOT assays. In addition, E5-CP vaccines elicited strong anti-tumor effects as showed by decreased tumor growth monitored by animal imaging. The tumor growth inhibition was comparable to those obtained with anti-E7 DNA vaccines. In conclusion, detection of E5 transcripts in clinical samples indicates that E5 is a possible target of immunotherapy. Data from pre-clinical model demonstrate that E5 genetic immunization is feasible, efficacious and could be utilized in clinical trials.

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Section: Discussionmentioning

confidence: 99%

HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

Paolini¹,

Curzio²,

Cordeiro

et al. 2016

Human Vaccines & Immunotherapeutics

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“…Dysregulated TGFβ signaling is associated with malignant progression of HPV-positive cervical dysplasia (33, 34), and HPV has been shown to promote cervical cancer by attenuating TGFβR1 signaling required for epithelial homeostasis at early stages of viral infection (35). Most importantly, genetic variants in TGFβ1 have also been shown to be associated with HPV-positive oropharyngeal cancer, with people carrying genotypes with TGFβ1 variants more than twice as likely to have an HPV-positive tumor as patients with the wild-type genotype (36).…”

Section: Discussionmentioning

confidence: 99%

TGFβ Receptor 1: An Immune Susceptibility Gene in HPV-Associated Cancer

et al. 2014

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Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical and oropharyngeal cancer. Because host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein–protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with oropharyngeal cancer. TGFβR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The TGFβR1 containing p38–MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFβR1 was overexpressed in oropharyngeal cancer, cervical cancer, and HPV+ head and neck cancer tumors. These concordant analyses implicate TGFβR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates TGFβR1/TGFβ signaling in the development of both oropharyngeal cancer and cervical cancer. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer.

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“…Down-regulation of TGF-β-RII gene expression and TGF-β\SMAD signaling.E5 attenuates TGF-β/SMAD-signalling by preventing TGF-β-RII gene expression. It also reduces SMAD phosphorylation and nuclear translocation [68]. …”

Section: Immune Modulation By E5 Oncoproteinmentioning

confidence: 99%

hrHPV E5 oncoprotein: immune evasion and related immunotherapies

Freitas

Oliveira

Júnior

et al. 2017

J Exp Clin Cancer Res

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The immune response is a key factor in the fight against HPV infection and related cancers, and thus, HPV is able to promote immune evasion through the expression of oncogenes. In particular, the E5 oncogene is responsible for modulation of several immune mechanisms, including antigen presentation and inflammatory pathways. Moreover, E5 was suggested as a promising therapeutic target, since there is still no effective medical therapy for the treatment of HPV-related pre-neoplasia and cancer. Indeed, several studies have shown good prospective for E5 immunotherapy, suggesting that it could be applied for the treatment of pre-cancerous lesions. Thus, insofar as the majority of cervical, oropharyngeal and anal cancers are caused by high-risk HPV (hrHPV), mainly by HPV16, the aim of this review is to discuss the immune pathways interfered by E5 oncoprotein of hrHPV highlighting the various aspects of the potential immunotherapeutic approaches.

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Expression of HPV16 E5 down-modulates the TGFbeta signaling pathway

Cited by 48 publications

References 24 publications

HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

HPV 16 E5 oncoprotein is expressed in early stage carcinogenesis and can be a target of immunotherapy

TGFβ Receptor 1: An Immune Susceptibility Gene in HPV-Associated Cancer

hrHPV E5 oncoprotein: immune evasion and related immunotherapies

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