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  • 1
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  • 2
    Keywords: CANCER ; PROTECTION ; BLOOD ; carcinoma ; evaluation ; human ; ALGORITHM ; RISK ; GENE ; INFECTION ; CARCINOGENESIS ; ANTIGEN ; BINDING ; ASSOCIATION ; LESIONS ; WOMEN ; cervical cancer ; HPV ; HPV16 ; VACCINE ; HLA class I ; EPITOPES ; intraepithelial neoplasia ; cervical carcinoma ; HLA ; PERIPHERAL-BLOOD ; E6 prototype ; E6 variant
    Abstract: Persistent infection with human papillomavirus (HPV), particularly HPV16, represents the prime risk factor in cervical carcinogenesis. HPV variants (e.g., within the E6 gene) together with immunogenetic factors of the host may be responsible either for effective viral clearance, or alternatively, for viral persistence. Peripheral blood from 27 HPV16 positive Swedish women with cervical carcinoma, who had previously been tested for HPV16 E6 variants, was used for human leukocyte antigen (HLA) class 1 typing. Women with HLA- B*44, HLA-B*51, or HLA-B*57 who were infected with the HPV16 E6 variant L83V had an approximately four- to fivefold increased risk for cancer compared with controls (odds ratio [OR] = 3.5, 95 % CI = 1.1-11.1, OR = 4.2, 95% CI = 1.19-14.69, or OR = 4.67, 95176 CI = 1.2-18.6, respectively). Epitope predictive algorithm with SYFPEITHI revealed that the variant at amino acid 83 affects the binding affinity in association with HLA- B*44. Interestingly, the HLA-B*15 allele seems protective because it was absent in HPV16 positive cancer. It is concluded that specific HLA class I alleles, combined with certain HPV16 E6 variants, may be crucial for immune surveillance in cervical carcinogenesis. The evaluation of associations of HLA alleles with HPV variants may be helpful in defining prognostic markers and in designing vaccines capable of mediating immune protection against HPV infection
    Type of Publication: Journal article published
    PubMed ID: 12691704
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  • 3
    Keywords: human ; PROTEIN ; PROTEINS ; CARCINOGENESIS ; SKIN ; papillomavirus ; SEQUENCE ; SEQUENCES ; SIGNAL-TRANSDUCTION ; REGION ; human papillomavirus ; TYPE-16 ; TRANSFORMATION ; HUMAN-PAPILLOMAVIRUS ; structural protein ; papillomaviruses ; TYPE-16 E5 ; EPIDERMODYSPLASIA-VERRUCIFORMIS
    Type of Publication: Journal article published
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  • 4
    Keywords: CANCER ; EXPRESSION ; tumor ; carcinoma ; CELL ; human ; KINASE ; PATHWAY ; GENE ; GENE-EXPRESSION ; GENES ; EPITHELIA ; DNA ; INFECTION ; CONTRAST ; papillomavirus ; LESIONS ; PROGRESSION ; gene expression ; ASSAY ; smoking ; inactivation ; PCR ; human papillomavirus ; HPV ; HUMAN-PAPILLOMAVIRUS ; SQUAMOUS-CELL CARCINOMA ; HEAD ; NECK ; squamous cell carcinoma ; TOBACCO ; ALCOHOL ; PREVALENCE ; GREECE ; head and neck ; ORAL-CANCER ; NECK-CANCER ; CELL CARCINOMA ; PRIMARY TUMORS ; head and neck cancers,tumor suppressor gene expression,human papillomavirus ; P16
    Abstract: To further characterize the biological and clinical role of molecular alterations involved in oral squamous carcinogenesis, the immunohistochemical expression level of two tumor suppressor genes, fragile histidine triad and p16(INK4a), in non-carcinomatous squamous epithelia and head and neck squamous cell carcinoma was determined. In addition, human papillomavirus infection determined by PCR assay and the use of alcohol and cigarettes were evaluated. In this study 28 non-carcinomatous squamous epithelia and 57 head and neck squamous cell carcinoma were considered. The expression levels of fragile histidine triad were lower in head and neck squamous cell carcinoma than in non-carcinomatous squamous epithelia. In contrast, p16(INK4a) is expressed in malignant lesions (51% of the cases analyzed), but not in non-carcinomatous squamous epithelia. No correlation between gene expression alterations of the two tumor suppressors was observed. PCR analysis showed that HPV DNA was present in 5 of the 57 malignant lesions analyzed (8.8%). None of the factors described above, despite changes in gene expression and HPV infection, appears to be associated with alcohol use and/or tobacco smoking and clinical outcome. Our data showed that fragile histidine triad and p16(INK4a) expression are altered in malignant lesions. Most likely, the decreasing levels of fragile histidine triad is directly involved in cancer development, while the accumulation of p16(INK4a) in head and neck squamous cell carcinoma may be the consequence of loss of functional tumor suppressor retinoblastoma pathway
    Type of Publication: Journal article published
    PubMed ID: 14719099
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  • 5
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; GROWTH ; human ; IN-VIVO ; PATHWAY ; PATHWAYS ; DEATH ; GENE ; GENES ; PROTEIN ; transcription ; MICE ; TIME ; MECHANISM ; CARCINOGENESIS ; SKIN ; E7 ; papillomavirus ; TRANSGENIC MICE ; p53 ; human papillomavirus ; E6 ; HUMAN-PAPILLOMAVIRUS ; RE ; TUMORIGENESIS ; downregulation ; function ; cutaneous HPV38 ; Delta Np73 ; E6 and E7
    Abstract: The E6 and E7 of the cutaneous human papillomavirus (HPV) type 38 immortalize primary human keratinocytes, an event normally associated with the inactivation of pathways controlled by the tumour suppressor p53. Here, we show for the first time that HPV38 alters p53 functions. Expression of HPV38 E6 and E7 in human keratinocytes or in the skin of transgenic mice induces stabilization of wild-type p53. This selectively activates the transcription of Delta Np73, an isoform of the p53-related protein p73, which in turn inhibits the capacity of p53 to induce the transcription of genes involved in growth suppression and apoptosis. Delta Np73 downregulation by an antisense oligonucleotide leads to transcriptional re-activation of p53-regulated genes and apoptosis. Our findings illustrate a novel mechanism of the alteration of p53 function that is mediated by a cutaneous HPV type and support the role of HPV38 and Delta Np73 in human carcinogenesis
    Type of Publication: Journal article published
    PubMed ID: 16397624
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  • 6
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; EXPRESSION ; CELL ; human ; IN-VIVO ; PATHWAY ; PATHWAYS ; VIVO ; transcription ; EFFICIENCY ; cell line ; LINES ; TIME ; RESPONSES ; DNA ; INFECTION ; MECHANISM ; KERATINOCYTES ; cell cycle ; CELL-CYCLE ; CELL-LINES ; CYCLE ; E7 ; papillomavirus ; SEQUENCE ; virus ; PROMOTER ; cervical cancer ; CERVICAL-CANCER ; CELL-LINE ; LINE ; human papillomavirus ; HPV ; E6 ; HUMAN KERATINOCYTES ; HUMAN-PAPILLOMAVIRUS ; ONCOPROTEIN ; IMMUNE-RESPONSE ; DOUBLE-STRANDED-RNA ; DIFFERENTIAL EXPRESSION ; cell lines ; TOLL-LIKE RECEPTORS ; RECOMBINANT ; RE ; keratinocyte ; VIRUS-INFECTION ; development ; EVENTS ; function ; LOSSES ; PLASMACYTOID DENDRITIC CELLS ; CANCERS ; in vivo ; immunology ; INHIBIT ; carcinogenic ; IMMUNE ACTIVATION ; IMMUNOLOGICAL RESPONSES ; TRANSFORMING PROPERTIES ; TYPE-18 ; VACCINIA-VIRUS
    Abstract: Cervical cancer development is linked to the persistent infection by high-risk mucosal human papillomaviruses (HPVs) types. The E6 and E7 major oncoproteins from this dsDNA virus play a key role in the deregulation of the cell cycle, apoptosis, and adaptive immune surveillance. In this study, we show for the first time that HPV type 16 (HPV16), the most carcinogenic type among the high-risk subgroup, interferes with innate immunity by affecting the expression of TLRs. Infection of human primary keratinocytes with HPV16 E6 and E7 recombinant retroviruses inhibits TLR9 transcription and hence functional loss of TLR9-regulated pathways. Similar findings were achieved in HPV16-positive cancer-derived cell lines and primary cervical cancers, demonstrating that this event occurs also in an in vivo context. Interestingly, E6 and E7 from the low-risk HPV type 6 are unable to down-regulate the TLR9 promoter. In addition, E6 and E7 from the high-risk HPV type 18, which are known to persist less competently in the host than HPV16, have reduced efficiency compared with HPV16 in inhibiting TLR9 transcription. Furthermore, a CpG motif derived from the HPV16 E6 DNA sequence activated TLR9, indicating this virus is able to initiate innate responses via the receptor it later down-regulates. This study reveals a novel mechanism used by HPV16 to suppress the host immune response by deregulating the TLR9 transcript, providing evidence that abolishing innate responses may be a crucial step involved in the carcinogenic events mediated by HPVs
    Type of Publication: Journal article published
    PubMed ID: 17312167
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  • 7
    Keywords: CANCER ; Germany ; PROTEIN ; MICE ; RESPONSES ; ANTIGEN ; papillomavirus ; ACID ; antibody ; FORM ; NEUTRALIZING ANTIBODIES ; virus ; cervical cancer ; CERVICAL-CANCER ; VIRUS-LIKE PARTICLES ; HPV ; PEPTIDES ; MONOCLONAL-ANTIBODIES ; VACCINE ; immune response ; AMINO-ACIDS ; IMMUNOGENICITY ; human papilloma virus ; POTENT ; AMINO-ACID ; N-TERMINUS ; MINOR CAPSID PROTEIN ; FORMULATION ; CANDIDATES ; thioredoxin ; PAPILLOMAVIRUS TYPES ; B-CELL EPITOPE ; CROSS-NEUTRALIZATION EPITOPE ; LINEAR EPITOPES ; Minor capsid protein L2
    Abstract: The minor capsid protein L2 is a promising candidate for the construction of an anti-human papillomavirus (HPV) broadly protective vaccine for the prophylaxis of cervical cancer. However, L2-derived peptides are usually poorly immunogenic and extensive knowledge on the most relevant(cross)neutralizing epitope(s) is still needed. We systematically examined the immunogenicity and Virus neutralization potential of six peptides encompassing the N-terminal (amino acids 1-120) region of HPV16 L2 (20-38; 28-42; 56-75: 64-81; 96-115; 108-120) using bacterial thioredoxin (Trx) as a novel peptide scaffold. Mice antisera generated by 19 different Trx-L2 peptide fusions hearing one or multiple copies of each peptide were analyzed. Internal fusion to thioredoxin conferred strong immunogenicity to all the tested peptides, with a trend toward art increased immunogenicity for the multipeptide vs. the monopeptide forms of the various antigens. All Trx-L2 peptides induced HPV16 neutralizing antibodies in some of the immunized mice, but neutralization titers differed by more than two orders of magnitude. Trx-L2(20-38) antisera were by far the most effective in HPV16 neutralization and did not differ significantly from those induced by a reference polypeptide covering the entire L2 (1-120) region. The same antisera were also the most effective when challenged against the non-cognate HPV 18, 58, 45 and 31 pseudovirions. The data identify L2(20-38) as the best (cross)neutralizing epitope among the six that were examined, and point to thioredoxin fusion derivatives of this peptide as excellent candidates for the formulation of a low-cost, broadly protective HPV vaccine. (C) 2009 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19368776
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  • 8
    Keywords: PEPTIDE ; INFECTION ; EFFICACY ; TYPE-16 ; VIRUS-LIKE PARTICLES ; MONOCLONAL-ANTIBODIES ; HPV16 ; VACCINE ; EPITOPE ; NEUTRALIZATION ; monoclonal antibody ; MINOR CAPSID PROTEIN ; pseudovirion ; prophylactic vaccine ; Immune epitope ; L2 protein
    Abstract: The N-terminal region of the human papillomavirus (HPV) L2 protein has been shown to contain immune epitopes able to induce the production of neutralizing and cross-neutralizing antibodies (Gambhira et al., 2007; Kawana et al., 1999). Using bacterial thioredoxin as a scaffold, we managed to enhance the immunogenicity of putative L2 neutralizing epitopes, but only a minor fraction of the resulting immune responses was found to be neutralizing (Rubio et al., 2009). To determine the recognition patterns for non-neutralizing, neutralizing and cross-neutralizing antibodies, we isolated and characterized a panel of 46 monoclonal antibodies directed against different HPV16 L2 epitopes. Four of such antibodies proved to be neutralizing, and two of them, both targeting the amino acid (aa) 20-38 region of L2, were found to cross-neutralize a broad range of papillomaviruses. The epitopes recognized by neutralizing and cross-neutralizing antibodies were mapped at high resolution and were found to be characterized by distinct recognition patterns. Even in the case of the L2 20-38 epitope, cross-neutralization of HPV31 pseudovirions proved to be extremely inefficient, and this was found to be primarily due to the lack of a proline residue at position 30. HPV16 specific amino acids in this region also appear to be responsible for the lack of cross-neutralizing activity, thus suggesting a potential immune escape mechanism. For the aa 71-80 region, instead, the data indicate that restriction of neutralization to HPV16 is due to sequence (or structural) differences laying outside of the epitope. Besides providing new insights on the molecular bases of L2-mediated immune reactivity, the present data may pave the way to novel vaccination approaches specifically evoking cross-neutralizing antibody responses.
    Type of Publication: Journal article published
    PubMed ID: 21074234
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  • 9
    Keywords: CANCER ; cell line ; DNA-DAMAGE ; STABILITY ; INDUCE APOPTOSIS ; REGULATES P73 ; HUMAN TUMORS ; C-ABL ; APOPTOTIC RESPONSE ; IKK-BETA ; P53-RELATED PROTEIN
    Abstract: Delta Np73 alpha, a dominant-negative inhibitor of p53 and p73, exhibits antiapoptotic and transforming activity in in vitro models and is often found to be upregulated in human cancers. The mechanisms involved in the regulation of Delta Np73 alpha protein levels in normal and cancer cells are poorly characterized. Here, we show that that I kappa B kinase beta (IKK beta) increases Delta Np73 alpha protein stability independently of its ability to activate NF-kappa B. IKK beta associates with and phosphorylates Delta Np73 alpha at serine 422 (S422), leading to its accumulation in the nucleus, where it binds and represses several p53-regulated genes. S422A mutation in Delta Np73 alpha abolished IKK beta-mediated stabilization and inhibition of p53-regulated gene expression. Inhibition of IKK beta activity by chemical inhibitors, overexpression of dominant-negative mutants, or gene silencing by siRNA also resulted in Delta Np73 alpha destabilization, which under these conditions was rapidly translocated into the cytoplasm and degraded by a calpain-mediated mechanism. We also present evidence for the IKK beta and Delta Np73 alpha cross talk in cancer-derived cell lines and primary cancers. Our data unveil a new mechanism involved in the regulation of the p73 and p53 network
    Type of Publication: Journal article published
    PubMed ID: 21482671
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  • 10
    Keywords: PATHWAY ; BINDING ; E7 ONCOPROTEIN ; C-MYC ; S-PHASE ; GROWTH ARREST ; GENE-PRODUCT ; INHIBITOR P27(KIP1) ; CELL-CYCLE REGULATION ; RETINOBLASTOMA-PROTEIN
    Abstract: In this study we show that E6 of human papillomavirus has the ability to deregulate the cell cycle G1/S transition. In rodent immortalized fibroblasts (NIH3T3) serum deprivation or over-expression of the cyclin-dependent kinase inhibitors, p16(INK4a) or p27(KIP1), leads to G1 cell cycle arrest. HPV16 E6 overcomes the antiproliferative signals, gaining the ability to drive serum-deprived and p16(INK4a) or p27(KIP1) over-expressing cells into S phase. E6 protein from the benign HPV type 1 displays a similar activity to HPV16 E6 to deregulate the G1/S transition. Thus, this activity appears to be conserved between E6 proteins from non-oncogenic and oncogenic HPV types. Furthermore, we show that HPV16 E6 is not able to circumvent a G1 arrest imposed by pRb mutant in which all CDK phosphorylation sites have been mutated. These data indicate that the viral protein acts upstream of pRb and its mechanism in promoting cell cycle progression is dependent on pRb phosphorylation. In summary, this study describes a novel biological function of HPV E6 and shows that the S phase entry, required for viral DNA replication, is not exclusively controlled by E7, but that E6 also is involved in this event.
    Type of Publication: Journal article published
    PubMed ID: 12173036
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