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1.
Mol Carcinog ; 60(5): 313-330, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33631046

RESUMO

Oncogenic high-risk human papillomavirus (HR-HPV) infection causes a majority of cases of cervical cancer and pre-cancerous cervical lesions. However, the mechanisms underlying the direct evolution from HPV-16/18-infected epithelium to cervical intraepithelial neoplasia (CIN) III, which can progress to cervical cancer, remain poorly identified. Here, we performed RNA-seq after laser capture microdissection, and found that APOBEC3B was highly expressed in cervical cancer specimens compared with CIN III with HPV-16/18 infection. Furthermore, immunohistochemical analysis confirmed that high levels of APOBEC3B were correlated with lymph node metastasis in cervical cancer. Subsequent experiments revealed that HPV-16 E6 could upregulate APOBEC3B through direct binding to the promoter of APOBEC3B in cervical cancer cells. Silencing of APOBEC3B by stable short hairpin RNA-mediated knockdown reduced the proliferative capacity of Caski and HeLa cells in vitro and in vivo, but had only a small effect on the migration and invasion of two cervical cancer cell lines. Finally, we identified the changes in gene expression following APOBEC3B silencing in Caski cells by microarray, demonstrating a biological link between APOBEC3B and CCND1 in cervical cancer cells. Importantly, through methyl-capture sequencing and pyrosequencing, APOBEC3B was found to affect the levels of the downstream protein Cyclin D1 (which is encoded by the CCND1 gene) through hypomethylation of the CCND1 promoter. In conclusion, our study supports HPV-16 E6-induced APOBEC3B expression associates with proliferation of cervical cancer cells and hypomethylation of Cyclin D1. Thus, APOBEC3B may be a potential therapeutic target in human cervical cancer.


Assuntos
Ciclina D1/genética , Citidina Desaminase/genética , Papillomavirus Humano 16/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Proteínas Oncogênicas Virais/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias do Colo do Útero/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Ilhas de CpG , Ciclina D1/metabolismo , Citidina Desaminase/metabolismo , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Células HeLa , Papillomavirus Humano 18/metabolismo , Humanos , Camundongos , Antígenos de Histocompatibilidade Menor/metabolismo , Transplante de Neoplasias , Regiões Promotoras Genéticas , Análise de Sequência de DNA , Análise de Sequência de RNA , Regulação para Cima , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia
2.
Clin Immunol ; 225: 108684, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33549834

RESUMO

Cervical cancer occurs as a result of the persistent infection of high-risk human papillomavirus (HPV). HPV16 oncoproteins E6 and E7 exert different and concerted pro-tumor actions in cell transformation and malignance maintenance in various m echanisms. Nanobody expressed as "intracellular antibodies" (intrabodies) can target intracellular antigens to hamper their function efficaciously and specifically. In this work, phage-display approach was employed to select the high affinity HPV16 E6-specific nanobody, nanobody Nb9 against HPV16 E6 was selected. Nb9 has high affinity (Kaff =6.3 × 108 M-) and can specifically bind endogenous HPV16 E6 protein in HPV16 positive CaSki and SiHa cells. In Nb9 overexpressed SiHa and CaSki cells, nucleus localization of HPV16 E6 was inhibited, p53 inactivation was prevented and increased apoptosis was observed. Moreover, tumor growth was inhibited in mouse xenograft model. Taken together, our results suggested that nanobody Nb9 could be a useful inhibitor for HPV16 E6 function and particularly appropriate for the treatment of HPV-associated disease.


Assuntos
Papillomavirus Humano 16/fisiologia , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/imunologia , Proteínas Repressoras/metabolismo , Anticorpos de Domínio Único/uso terapêutico , Neoplasias do Colo do Útero/imunologia , Animais , Linhagem Celular Tumoral , Técnicas de Visualização da Superfície Celular , Feminino , Xenoenxertos , Humanos , Espaço Intracelular/metabolismo , Camundongos , Camundongos Nus , Proteínas Oncogênicas Virais/imunologia , Proteínas Repressoras/imunologia , Anticorpos de Domínio Único/isolamento & purificação , Carga Tumoral , Neoplasias do Colo do Útero/terapia
3.
PLoS Pathog ; 17(1): e1009216, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33481911

RESUMO

Intracellular pathogens have evolved to utilize normal cellular processes to complete their replicative cycles. Pathogens that interface with proliferative cell signaling pathways risk infections that can lead to cancers, but the factors that influence malignant outcomes are incompletely understood. Human papillomaviruses (HPVs) predominantly cause benign hyperplasia in stratifying epithelial tissues. However, a subset of carcinogenic or "high-risk" HPV (hr-HPV) genotypes are etiologically linked to nearly 5% of all human cancers. Progression of hr-HPV-induced lesions to malignancies is characterized by increased expression of the E6 and E7 oncogenes and the oncogenic functions of these viral proteins have been widely studied. Yet, the mechanisms that regulate hr-HPV oncogene transcription and suppress their expression in benign lesions remain poorly understood. Here, we demonstrate that EGFR/MEK/ERK signaling, influenced by epithelial contact inhibition and tissue differentiation cues, regulates hr-HPV oncogene expression. Using monolayer cells, epithelial organotypic tissue models, and neoplastic tissue biopsy materials, we show that cell-extrinsic activation of ERK overrides cellular control to promote HPV oncogene expression and the neoplastic phenotype. Our data suggest that HPVs are adapted to use the EGFR/MEK/ERK signaling pathway to regulate their productive replicative cycles. Mechanistic studies show that EGFR/MEK/ERK signaling influences AP-1 transcription factor activity and AP-1 factor knockdown reduces oncogene transcription. Furthermore, pharmacological inhibitors of EGFR, MEK, and ERK signaling quash HPV oncogene expression and the neoplastic phenotype, revealing a potential clinical strategy to suppress uncontrolled cell proliferation, reduce oncogene expression and treat HPV neoplasia.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Neoplasias do Colo do Útero/virologia , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Terapia de Alvo Molecular , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/terapia
4.
Cancer Lett ; 497: 14-27, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33010383

RESUMO

Human papillomavirus (HPV) is the etiological agent of cervical cancer; however, the mechanisms underlying HPV-mediated carcinogenesis remain poorly understood. Here, we showed that nuclear receptor related-1 protein (Nurr1) was upregulated in primary cervical cancer tissue-derived spheroid cells and HPV-positive cell lines, and Nurr1 upregulation was correlated with cancer grade. Nurr1 promoted cell proliferation, migration, invasion, and anchorage-independent cell growth. In addition to its effect on cancer aggressiveness, Nurr1 enhanced the self-renewal ability of cells in vitro and in vivo, underscoring the importance of Nurr1 in maintaining the stemness of cancer stem-like cells (CSLCs). Mechanistically, Nurr1 independently activated the MEK/ERK and PI3K/Akt/mTOR signaling cascades. The MEK inhibitor trametinib (GSK) and PI3K/mTOR dual inhibitor dactolisib (BEZ) were shown to abrogate Nurr1-augmented tumorigenesis by upregulating p21 and p27 expression and by suppressing MMP9 and KLF4 expression. We provided further evidence that BEZ, but not GSK, could abolish Nurr1-enhanced radioresistance, suggesting its potential value for radiosensitizing CSLCs in the clinical setting. This study highlights the unprecedented roles of Nurr1 and elucidates mechanisms by which Nurr1 promotes tumor progression and radioresistance, providing a novel therapeutic strategy for cervical cancer treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Células-Tronco Neoplásicas/patologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Tolerância a Radiação , Neoplasias do Colo do Útero/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Proteínas Oncogênicas Virais/genética , Papillomaviridae/fisiologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/radioterapia , Neoplasias do Colo do Útero/virologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
PLoS One ; 15(12): e0242465, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33332365

RESUMO

Peroxiredoxin 2 (PRDX2) is upregulated in various cancers including oral squamous cell carcinoma (OSCC). It is a known tumor promoter in some cancers, but its role in OSCC is unclear. This study aimed to investigate the effect of arecoline, an alkaloid of the betel nut, and human papillomavirus type 16 (HPV16) E6/E7 oncoproteins on induction of PRDX2 expression, and also the effects of PRDX2 overexpression in oral cell lines. Levels of PRDX2 protein were determined using western blot analysis of samples of exfoliated normal oral cells (n = 75) and oral lesion cells from OSCC cases (n = 75). Some OSCC cases were positive for HPV infection and some patients had a history of betel quid chewing. To explore the level of PRDX2 by western blot, the proteins were extracted from oral cell lines that were treated with arecoline or retroviruses containing HPV16 E6 gene and HPV16 E6/E7 expressing vector. For analysis of PRDX2 functions, cell proliferation, cell-cycle progression, apoptosis and migration was compared between oral cells overexpressing PRDX2 and cells with PRDX2-knockdown. PRDX2 expression levels tended to be higher in OSCC samples that were positive for HPV infection and had history of betel quid chewing. Arecoline treatment in vitro at low concentrations and overexpression of HPV16 E6 or E6/E7 in oral cells induced PRDX2 overexpression. Interestingly, in oral cells, PRDX2 promoted cell proliferation, cell-cycle progression (G2/M phase), cell migration and inhibited apoptosis. Upregulation of PRDX2 in oral cells was induced by arecoline and HPV16 oncoproteins and promoted growth of OSCC cells.


Assuntos
Arecolina/farmacologia , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Bucais/genética , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/genética , Peroxirredoxinas/genética , Proteínas Repressoras/genética , Idoso , Apoptose/genética , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Papillomavirus Humano 16/química , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/enzimologia , Neoplasias Bucais/patologia , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Peroxirredoxinas/antagonistas & inibidores , Peroxirredoxinas/metabolismo , Plasmídeos/química , Plasmídeos/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais , Transfecção
6.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333786

RESUMO

Although the effect of hypoxia on p53 in human papillomavirus (HPV)-positive cancer cells has been studied for decades, the impact of p53 regulation on downstream targets and cellular adaptation processes during different periods under hypoxia remains elusive. Here, we show that, despite continuous repression of HPV16 E6/E7 oncogenes, p53 did not instantly recover but instead showed a biphasic regulation marked by further depletion within 24 h followed by an increase at 72 h. Of note, during E6/E7 oncogene suppression, lysosomal degradation antagonizes p53 reconstitution. Consequently, the transcription of p53 responsive genes associated with senescence (e.g., PML and YPEL3) cannot be upregulated. In contrast, downstream genes involved in autophagy (e.g., DRAM1 and BNIP3) were activated, allowing the evasion of senescence under hypoxic conditions. Hence, dynamic regulation of p53 along with its downstream network of responsive genes favors cellular adaptation and enhances cell survival, although the expression of the viral E6/E7-oncogenes as drivers for proliferation remained inhibited under hypoxia.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Papillomavirus Humano 16/metabolismo , Infecções por Papillomavirus/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/genética , Hipóxia Celular/genética , Senescência Celular/genética , Regulação para Baixo , Feminino , Papillomavirus Humano 16/genética , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/genética , Proteína da Leucemia Promielocítica/genética , Proteína da Leucemia Promielocítica/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Interferente Pequeno , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologia
7.
Gene ; 760: 145003, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32739587

RESUMO

Imiquimod (IMQ) is approved as a first-line treatment for genital warts caused by human papillomavirus (HPV) infection. However, the recurrence rate is very high. HPV E7 protein plays a critical role in HPV immune escape. However, the role of HPV11 E7 protein in genital warts recurrence during IMQ treatment is not clear. Here, we found that the expression profile of NHEK cells was obviously changed after IMQ treatment, and a large number of genes encoding cytokines and genes involved in cytokine-mediated signaling pathways and cellular metabolic signaling pathways were up- or downregulated. HPV11E7 overexpression inhibited the IMQ-induced production of of multiple chemokines and colony-stimulating factors in NHEK cells. Furthermore, we found that HPV11E7 could impair the activation of mitogen-activated protein kinase (MAPK) signaling pathway. Therefore, our results suggested that HPV11 E7 diminishes the production of chemokines, colony-stimulating factors and other cytokines via inhibition of the MAPK signaling pathway, which suppresses the therapeutic effect of IMQ and promotes the recurrence of diseases, such as condyloma acuminatum.


Assuntos
Imiquimode/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Quimiocinas/biossíntese , Quimiocinas/genética , Quimiocinas/metabolismo , Fatores Estimuladores de Colônias/biossíntese , Fatores Estimuladores de Colônias/metabolismo , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Papillomavirus Humano 11/metabolismo , Humanos , Imiquimode/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Oncogênicas Virais/imunologia , Infecções por Papillomavirus/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
8.
PLoS Pathog ; 16(8): e1008792, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32813746

RESUMO

Tumor suppressors can exert pro-proliferation functions in specific contexts. In the beta human papillomavirus type 38 (HPV38) experimental model, the viral proteins E6 and E7 promote accumulation of a wild-type (WT) p53 form in human keratinocytes (HKs), promoting cellular proliferation. Inactivation of p53 by different means strongly decreases the proliferation of HPV38 E6/E7 HKs. This p53 form is phosphorylated at S392 by the double-stranded RNA-dependent protein kinase PKR, which is highly activated by HPV38. PKR-mediated S392 p53 phosphorylation promotes the formation of a p53/DNMT1 complex, which inhibits expression of integrin alpha 1 (ITGA1), a repressor of epidermal growth factor receptor (EGFR) signaling. Ectopic expression of ITGA1 in HPV38 E6/E7 HKs promotes EGFR degradation, inhibition of cellular proliferation, and cellular death. Itga1 expression was also inhibited in the skin of HPV38 transgenic mice that have an elevated susceptibility to UV-induced skin carcinogenesis. In summary, these findings reveal the existence of a specific WT p53 form that displays pro-proliferation properties.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Proliferação de Células , Queratinócitos/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/complicações , Proteínas Repressoras/metabolismo , Neoplasias Cutâneas/etiologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Células Cultivadas , Regulação para Baixo , Humanos , Queratinócitos/imunologia , Queratinócitos/virologia , Camundongos , Camundongos Transgênicos , Proteínas Oncogênicas Virais/genética , Papillomaviridae/isolamento & purificação , Proteínas E7 de Papillomavirus/genética , Infecções por Papillomavirus/virologia , Proteínas Repressoras/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Proteína Supressora de Tumor p53/genética
9.
PLoS Pathog ; 16(6): e1008624, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32555725

RESUMO

Human papillomaviruses (HPV) are a major cause of malignancy worldwide. They are the aetiological agents of almost all cervical cancers as well as a sub-set of other anogenital and head and neck cancers. Hijacking of host cellular pathways is essential for virus pathogenesis; however, a major challenge remains to identify key host targets and to define their contribution to HPV-driven malignancy. The Hippo pathway regulates epithelial homeostasis by down-regulating the function of the transcription factor YAP. Increased YAP expression has been observed in cervical cancer but the mechanisms driving this increase remain unclear. We found significant down-regulation of the master Hippo regulatory kinase STK4 (also termed MST1) in cervical disease samples and cervical cancer cell lines compared with healthy controls. Re-introduction of STK4 inhibited the proliferation of HPV positive cervical cells and this corresponded with decreased YAP nuclear localization and decreased YAP-dependent gene expression. The HPV E6 and E7 oncoproteins maintained low STK4 expression in cervical cancer cells by upregulating the oncomiR miR-18a, which directly targeted the STK4 mRNA 3'UTR. Interestingly, miR-18a knockdown increased STK4 expression and activated the Hippo pathway, significantly reducing cervical cancer cell proliferation. Our results identify STK4 as a key cervical cancer tumour suppressor, which is targeted via miR-18a in HPV positive tumours. Our study indicates that activation of the Hippo pathway may offer a therapeutically beneficial option for cervical cancer treatment.


Assuntos
Transformação Celular Viral , MicroRNAs/metabolismo , Papillomaviridae/metabolismo , Infecções por Papillomavirus/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , RNA Neoplásico/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Neoplasias do Colo do Útero/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Proteínas Serina-Treonina Quinases/genética , RNA Neoplásico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia
10.
PLoS Pathog ; 16(4): e1008468, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32298395

RESUMO

Octamer binding transcription factor-4 (Oct4), is highly expressed in stem cells and has indispensable roles in pluripotency and cellular reprogramming. In contrast to other factors used for cellular reprogramming, a role for Oct4 outside embryonic stem cells has been elusive and highly controversial. Emerging evidence implicates Oct4 in the carcinogenic process, but the mechanism through which Oct4 may be functioning in cancers is not fully appreciated. Here, we provide evidence that Oct4 is expressed in human cervical cancer and this expression correlates with the presence of the human papillomavirus (HPV) oncogenes E6 and E7. Surprisingly, the viral oncogenes can complement exogenously provided Oct4 in reprogramming assays, providing functional validation for their ability to activate Oct4 transcription in Mouse Embryonic Fibroblasts (MEFs). To interrogate potential roles of Oct4 in cervical cancers we knocked-down Oct4 in HPV(+) (HeLa & CaSki) and HPV(-) (C33A) cervical cancer cell lines and found that Oct4 knockdown attenuated clonogenesis, only in the HPV(+) cells. More unexpectedly, cell proliferation and migration, were differentially affected in HPV(+) and HPV(-) cell lines. We provide evidence that Oct4 interacts with HPV E7 specifically at the CR3 region of the E7 protein and that introduction of the HPV oncogenes in C33A cells and human immortalised keratinocytes generates Oct4-associated transcriptional and phenotypic patterns, which mimic those seen in HPV(+) cells. We propose that a physical interaction of Oct4 with E7 regulates its activity in HPV(+) cervical cancers in a manner not seen in other cancer types.


Assuntos
Fator 3 de Transcrição de Octâmero/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/virologia , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Feminino , Células HeLa , Humanos , Fator 3 de Transcrição de Octâmero/biossíntese , Fator 3 de Transcrição de Octâmero/genética , Proteínas Oncogênicas Virais/metabolismo , Oncogenes/fisiologia , Papillomaviridae/genética , Papillomaviridae/metabolismo , Proteínas E7 de Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Proteínas Repressoras/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
11.
J Virol ; 94(12)2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32238586

RESUMO

Beta genus human papillomaviruses (ß-HPVs) cause cutaneous squamous cell carcinomas (cSCCs) in a subset of immunocompromised patients. However, ß-HPVs are not necessary for tumor maintenance in the general population. Instead, they may destabilize the genome in the early stages of cancer development. Supporting this idea, ß-HPV's 8E6 protein attenuates p53 accumulation after failed cytokinesis. This paper offers mechanistic insight into how ß-HPV E6 causes this change in cell signaling. An in silico screen and characterization of HCT 116 cells lacking p300 suggested that the histone acetyltransferase is a negative regulator of Hippo pathway (HP) gene expression. HP activation restricts growth in response to stimuli, including failed cytokinesis. Loss of p300 resulted in increased HP gene expression, including proproliferative genes associated with HP inactivation. ß-HPV 8E6 expression recapitulates some of these phenotypes. We used a chemical inhibitor of cytokinesis (dihydrocytochalasin B [H2CB]) to induce failed cytokinesis. This system allowed us to show that ß-HPV 8E6 reduced activation of large tumor suppressor kinase (LATS), an HP kinase. LATS is required for p53 accumulation following failed cytokinesis. These phenotypes were dependent on ß-HPV 8E6 destabilizing p300 and did not completely attenuate the HP. It did not alter H2CB-induced nuclear exclusion of the transcription factor YAP. ß-HPV 8E6 also did not decrease HP activation in cells grown to a high density. Although our group and others have previously described inhibition of DNA repair, to the best of our knowledge, this marks the first time that a ß-HPV E6 protein has been shown to hinder HP signaling.IMPORTANCE ß-HPVs contribute to cSCC development in immunocompromised populations. However, it is unclear if these common cutaneous viruses are tumorigenic in the general population. Thus, a more thorough investigation of ß-HPV biology is warranted. If ß-HPV infections do promote cSCCs, they are hypothesized to destabilize the cellular genome. In vitro data support this idea by demonstrating the ability of the ß-HPV E6 protein to disrupt DNA repair signaling events following UV exposure. We show that ß-HPV E6 more broadly impairs cellular signaling, indicating that the viral protein dysregulates the HP. The HP protects genome fidelity by regulating cell growth and apoptosis in response to a myriad of deleterious stimuli, including failed cytokinesis. After failed cytokinesis, ß-HPV 8E6 attenuates phosphorylation of the HP kinase (LATS). This decreases some, but not all, HP signaling events. Notably, ß-HPV 8E6 does not limit senescence associated with failed cytokinesis.


Assuntos
Citocinese/genética , Interações Hospedeiro-Patógeno/genética , Proteínas Oncogênicas Virais/genética , Papillomaviridae/genética , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocalasina B/análogos & derivados , Citocalasina B/farmacologia , Citocinese/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Proteína p300 Associada a E1A/deficiência , Proteína p300 Associada a E1A/genética , Regulação da Expressão Gênica , Células HCT116 , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/virologia , Proteínas Oncogênicas Virais/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/virologia , Papillomaviridae/metabolismo , Fenótipo , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
12.
Proc Natl Acad Sci U S A ; 117(11): 6121-6128, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123072

RESUMO

Virus replication requires critical interactions between viral proteins and cellular proteins that mediate many aspects of infection, including the transport of viral genomes to the site of replication. In human papillomavirus (HPV) infection, the cellular protein complex known as retromer binds to the L2 capsid protein and sorts incoming virions into the retrograde transport pathway for trafficking to the nucleus. Here, we show that short synthetic peptides containing the HPV16 L2 retromer-binding site and a cell-penetrating sequence enter cells, sequester retromer from the incoming HPV pseudovirus, and inhibit HPV exit from the endosome, resulting in loss of viral components from cells and in a profound, dose-dependent block to infection. The peptide also inhibits cervicovaginal HPV16 pseudovirus infection in a mouse model. These results confirm the retromer-mediated model of retrograde HPV entry and validate intracellular virus trafficking as an antiviral target. More generally, inhibiting virus replication with agents that can enter cells and disrupt essential protein-protein interactions may be applicable in broad outline to many viruses.


Assuntos
Proteínas do Capsídeo/metabolismo , Peptídeos Penetradores de Células/farmacologia , Papillomavirus Humano 16/efeitos dos fármacos , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/tratamento farmacológico , Internalização do Vírus/efeitos dos fármacos , Animais , Peptídeos Penetradores de Células/uso terapêutico , Colo do Útero/virologia , Modelos Animais de Doenças , Feminino , Células HEK293 , Células HeLa , Papillomavirus Humano 16/fisiologia , Humanos , Camundongos , Infecções por Papillomavirus/virologia , Ligação Proteica/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Vagina/virologia
13.
Mem Inst Oswaldo Cruz ; 115: e190405, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32187327

RESUMO

BACKGROUND: High-risk human papillomaviruses (HR-HPVs) are the etiological agents of cervical cancer. Among them, types 16 and 18 are the most prevalent worldwide. The HPV genome encodes three oncoproteins (E5, E6, and E7) that possess a high transformation potential in culture cells when transduced simultaneously. In the present study, we analysed how these oncoproteins cooperate to boost key cancer cell features such as uncontrolled cell proliferation, invasion potential, and cellular redox state imbalance. Oxidative stress is known to contribute to the carcinogenic process, as reactive oxygen species (ROS) constitute a potentially harmful by-product of many cellular reactions, and an efficient clearance mechanism is therefore required. Cells infected with HR-HPVs can adapt to oxidative stress conditions by upregulating the formation of endogenous antioxidants such as catalase, glutathione (GSH), and peroxiredoxin (PRX). OBJECTIVES: The primary aim of this work was to study how these oncoproteins cooperate to promote the development of certain cancer cell features such as uncontrolled cell proliferation, invasion potential, and oxidative stress that are known to aid in the carcinogenic process. METHODS: To perform this study, we generated three different HaCaT cell lines using retroviral transduction that stably expressed combinations of HPV-18 oncogenes that included HaCaT E5-18, HaCaT E6/E7-18, and HaCaT E5/E6/E7-18. FINDINGS: Our results revealed a statistically significant increment in cell viability as measured by MTT assay, cell proliferation, and invasion assays in the cell line containing the three viral oncogenes. Additionally, we observed that cells expressing HPV-18 E5/E6/E7 exhibited a decrease in catalase activity and a significant augmentation of GSH and PRX1 levels relative to those of E5, E6/E7, and HaCaT cells. MAIN CONCLUSIONS: This study demonstrates for the first time that HPV-18 E5, E6, and E7 oncoproteins can cooperate to enhance malignant transformation.


Assuntos
Transformação Celular Viral/genética , Proteínas de Ligação a DNA/metabolismo , Papillomavirus Humano 18/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Linhagem Celular Tumoral/virologia , Proliferação de Células , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Oxirredução
14.
Nanoscale ; 12(9): 5501-5506, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32091054

RESUMO

In order to improve the cell-imaging ability, and particularly, to extend the bio-application of AIEgen, human papillomavirus (HPV) capsid protein L1 was assembled with the complex of DNA and aggregation-induced emission fluorogen 9,10-distyrylhydrazine (DSAI), where the virus-like particles (VLPs) of HPV encapsulate the complex via electrostatic interaction. The co-assembled nanoparticles, DSAI-DNA@VLPs, showed homogeneous size (∼53 nm), enhanced fluorescence (8 × 2.5-fold), considerable stability (anti-DNase digestion), improved biocompatibility and commendable protection for the DSAI-DNA complex, ensuring virtual brighter imaging in live cells, both for HeLa and normal 293T cell lines.


Assuntos
Proteínas do Capsídeo/química , Corantes Fluorescentes/química , Hidrazinas/química , Proteínas Oncogênicas Virais/química , Proteínas do Capsídeo/metabolismo , DNA/química , Células HEK293 , Células HeLa , Humanos , Microscopia Confocal , Nanopartículas/química , Proteínas Oncogênicas Virais/metabolismo , Tamanho da Partícula
15.
Int J Oral Sci ; 12(1): 3, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911577

RESUMO

High-risk human papillomaviruses (HPVs) are involved in the development of several human cancers, including oropharyngeal squamous cell carcinomas. However, many studies have demonstrated that HPV alone is not sufficient for the oncogenic transformation of normal human epithelial cells, indicating that additional cofactors are required for the oncogenic conversion of HPV-infected cells. Inasmuch as chronic inflammation is also closely associated with carcinogenesis, we investigated the effect of chronic exposure to tumor necrosis factor α (TNFα), the major proinflammatory cytokine, on oncogenesis in two immortalized oral keratinocyte cell lines, namely, HPV16-immortalized and human telomerase reverse transcriptase (hTERT)-immortalized cells. TNFα treatment led to the acquisition of malignant growth properties in HPV16-immortalized cells, such as (1) calcium resistance, (2) anchorage independence, and (3) increased cell proliferation in vivo. Moreover, TNFα increased the cancer stem cell-like population and stemness phenotype in HPV16-immortalized cells. However, such transforming effects were not observed in hTERT-immortalized cells, suggesting an HPV-specific role in TNFα-promoted oncogenesis. We also generated hTERT-immortalized cells that express HPV16 E6 and E7. Chronic TNFα exposure successfully induced the malignant growth and stemness phenotype in the E6-expressing cells but not in the control and E7-expressing cells. We further demonstrated that HPV16 E6 played a key role in TNFα-induced cancer stemness via suppression of the stemness-inhibiting microRNAs miR-203 and miR-200c. Overexpression of miR-203 and miR-200c suppressed cancer stemness in TNFα-treated HPV16-immortalized cells. Overall, our study suggests that chronic inflammation promotes cancer stemness in HPV-infected cells, thereby promoting HPV-associated oral carcinogenesis.


Assuntos
Carcinoma de Células Escamosas/genética , Papillomavirus Humano 16/metabolismo , MicroRNAs/metabolismo , Neoplasias Bucais/genética , Boca/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/virologia , Telomerase/genética , Fator de Necrose Tumoral alfa/metabolismo , Carcinogênese/genética , Carcinogênese/imunologia , Carcinoma de Células Escamosas/patologia , Transformação Celular Viral/genética , Regulação da Expressão Gênica , Genes Virais , Papillomavirus Humano 16/genética , Humanos , MicroRNAs/genética , Boca/virologia , Neoplasias Bucais/patologia , Proteínas Oncogênicas Virais/genética , Papillomaviridae/genética , Telomerase/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
16.
Sci Rep ; 10(1): 1097, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974410

RESUMO

p53 and aldehyde dehydrogenase (ALDH) have been implicated in key tumorigenesis processes including cancer initiating cell (CIC) maintenance; however, the relationship between these two mediators remains poorly defined. In this study, ALDH isoform expression diversity was revealed in CICs with disparate p53 functional states: gain of function, high risk p53 mutation (p53HRmut) and wildtype p53 (p53WT) inactivated by the human papillomavirus 16 (HPV16) E6 oncogene. Interrogation of head and neck squamous cell carcinoma (HNSCC) cell lines and patient tumors showed that HPV16+/p53WT cases have higher ALDH variance score (AVS), a measure of tumor ALDH isoform expression diversity, compared to HPV-/p53HRmut cases (p = 0.03). AVS and several individual ALDH isoforms were associated with prognosis in HPV16+/p53WT HNSCC but not in HPV-/p53HRmut HNSCC. Knockdown of the dominant ALDH isoform in high AVS HNSCC depleted the CIC pool in vitro and in vivo. Our results demonstrate that p53 functional states are associated with distinct ALDH isoform transcriptomic signatures. Moreover, tumor ALDH profiling may provide insight on which ALDH isoform to target in high AVS HNSCC tumors to deplete the CIC population.


Assuntos
Aldeído Desidrogenase/genética , Infecções por Papillomavirus/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Aldeído Desidrogenase/metabolismo , Animais , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/fisiologia , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Camundongos , Células-Tronco Neoplásicas/metabolismo , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/enzimologia , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transcriptoma , Proteína Supressora de Tumor p53/genética
17.
PLoS Pathog ; 16(1): e1008295, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31971989

RESUMO

The HECT domain E3 ubiquitin ligase E6AP (UBE3A) is critical for the development of human papillomavirus (HPV) associated cancers, the neurodevelopment disorder Angelman Syndrome, and some cases of autism spectrum disorders. How E6AP recognizes its cellular targets and how its ubiquitin ligase activity is triggered remain poorly understood, and HPV E6 proteins are models for these processes. We examined diverse E6 proteins from human and non-human papillomaviruses and identified two different modes of interaction between E6 and E6AP. In Type I interactions, E6 can interact directly with the LXXLL peptide motif alone of E6AP (isolated from the rest of E6AP), and then recruit cellular substrates such as p53. In Type II interactions, E6 proteins require additional auxiliary regions of E6AP in either the amino terminus or in the carboxy-terminal HECT domain to interact with the LXXLL peptide motif of E6AP. A region of E6AP amino-terminal to the LXXLL peptide motif both augments association with E6 proteins and is required for E6 proteins to trigger ubiquitin ligase activity in the carboxy-terminal HECT ubiquitin ligase domain of E6AP. In Type I interactions, E6 can associate with E6AP and recruit p53, but a Type II interaction is required for the degradation of p53 or NHERF1. Interestingly, different E6 proteins varied in E6AP auxiliary regions that contributed to enhanced association, indicating evolutionary drift in the formation of Type II interactions. This classification of E6-E6AP interaction types and identification of a region in the E6AP amino terminus that is important for both E6 association and stimulation of ubiquitin ligase activity will inform future structural data of the E6-E6AP complex and future studies aiming to interfere with the activity of the E6-E6AP complex.


Assuntos
Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/metabolismo , Infecções por Papillomavirus/enzimologia , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/metabolismo , Motivos de Aminoácidos , Humanos , Proteínas Oncogênicas Virais/genética , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Ligação Proteica , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Trocadores de Sódio-Hidrogênio/genética , Trocadores de Sódio-Hidrogênio/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/genética
18.
Microb Pathog ; 139: 103923, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31836496

RESUMO

Oncoprotein E5 is gaining popularity with time as the third transforming protein of Human Papillomavirus (HPV). Extensive proliferation is the distinguished feature of developing cancers, and E5 is able to stimulate keratinocytes proliferation via upregulation of EGFR signaling pathway. Thus E5 is thought to indirectly contribute to the completion of the viral life-cycle by generating the adequate cellular environment. By amplifying EGFR signaling E5 delays differentiation and allows hyperproliferation of keratinocytes which otherwise would have followed a normal differentiation pathway. Thus exploring the mechanisms by which HPV E5 regulates signaling by EGFR receptors in detail suggest new ways of inhibiting HPV-mediated disease progression.


Assuntos
Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/crescimento & desenvolvimento , Papillomaviridae/metabolismo , Infecções por Papillomavirus/virologia , Animais , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Proteínas Oncogênicas Virais/genética , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Transdução de Sinais
19.
J Virol ; 94(4)2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31776268

RESUMO

Subversion of innate immunity by oncoviruses, such as human papillomavirus (HPV), favors carcinogenesis because the mechanism(s) of viral immune evasion can also hamper cancer immunosurveillance. Previously, we demonstrated that high-risk (hr) HPVs trigger simultaneous epigenetic silencing of multiple effectors of innate immunity to promote viral persistence. Here, we expand on those observations and show that the HPV E7 oncoprotein upregulates the H3K9-specific methyltransferase, whose action shuts down the host innate immune response. Specifically, we demonstrate that SUV39H1 contributes to chromatin repression at the promoter regions of the viral nucleic acid sensors RIG-I and cGAS and the adaptor molecule STING in HPV-transformed cells. Inhibition of SUV39H1 leads to transcriptional activation of these genes, especially RIG-I, followed by increased beta interferon (IFN-ß) and IFN-λ1 production after poly(dA·dT) or RIG-I agonist M8 transfection. Collectively, our findings provide new evidence that the E7 oncoprotein plays a central role in dampening host innate immunity and raise the possibility that targeting the downstream effector SUV39H1 or the RIG-I pathway is a viable strategy to treat viral and neoplastic disease.IMPORTANCE High-risk HPVs are major viral human carcinogens responsible for approximately 5% of all human cancers. The growth of HPV-transformed cells depends on the ability of viral oncoproteins to manipulate a variety of cellular circuits, including those involved in innate immunity. Here, we show that one of these strategies relies on E7-mediated transcriptional activation of the chromatin repressor SUV39H1, which then promotes epigenetic silencing of RIG-I, cGAS, and STING genes, thereby shutting down interferon secretion in HPV-transformed cells. Pharmacological or genetic inhibition of SUV39H1 restored the innate response in HPV-transformed cells, mostly through activation of RIG-I signaling. We also show that IFN production upon transfection of poly(dA·dT) or the RIG-I agonist M8 predominantly occurs through RIG-I signaling. Altogether, the reversible nature of the modifications associated with E7-mediated SUV39H1 upregulation provides a rationale for the design of novel anticancer and antiviral therapies targeting these molecules.


Assuntos
Metiltransferases/metabolismo , Papillomaviridae/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Repressoras/metabolismo , Linhagem Celular , Proteína DEAD-box 58/metabolismo , Epigênese Genética/genética , Células HEK293 , Células HeLa , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Evasão da Resposta Imune/genética , Evasão da Resposta Imune/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Interferon beta/metabolismo , Queratinócitos/virologia , Proteínas de Membrana/metabolismo , Metiltransferases/genética , Nucleotidiltransferases/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/patogenicidade , Proteínas E7 de Papillomavirus/fisiologia , Infecções por Papillomavirus/virologia , Proteínas Repressoras/genética , Transdução de Sinais/genética , Ativação Transcricional/genética
20.
Cancer Res ; 80(4): 732-746, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31848196

RESUMO

There is a critical need to understand mechanisms of resistance and to develop combinatorial strategies to improve responses to checkpoint blockade immunotherapy (CBI). Here, we uncover a novel mechanism by which the human papillomavirus (HPV) inhibits the activity of CBI in head and neck squamous cell carcinoma (HNSCC). Using orthotopic HNSCC models, we show that radiation combined with anti-PD-L1 immunotherapy significantly enhanced local control, CD8+ memory T cells, and induced preferential T-cell homing via modulation of vascular endothelial cells. However, the HPV E5 oncoprotein suppressed immune responses by downregulating expression of major histocompatibility complex and interfering with antigen presentation in murine models and patient tumors. Furthermore, tumors expressing HPV E5 were rendered entirely resistant to anti-PD-L1 immunotherapy, and patients with high expression of HPV16 E5 had worse survival. The antiviral E5 inhibitor rimantadine demonstrated remarkable single-agent antitumor activity. This is the first report that describes HPV E5 as a mediator of resistance to anti-PD-1/PD-L1 immunotherapy and demonstrates the antitumor activity of rimantadine. These results have broad clinical relevance beyond HNSCC to other HPV-associated malignancies and reveal a powerful mechanism of HPV-mediated immunosuppression, which can be exploited to improve response rates to checkpoint blockade. SIGNIFICANCE: This study identifies a novel mechanism of resistance to anti-PD-1/PD-L1 immunotherapy mediated by HPV E5, which can be exploited using the HPV E5 inhibitor rimantadine to improve outcomes for head and neck cancer patients. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/4/732/F1.large.jpg.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias de Cabeça e Pescoço/terapia , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/terapia , Rimantadina/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Adolescente , Adulto , Idoso , Animais , Apresentação do Antígeno/efeitos dos fármacos , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral/transplante , Quimiorradioterapia/métodos , Estudos de Coortes , Modelos Animais de Doenças , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/virologia , Voluntários Saudáveis , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 16/metabolismo , Papillomavirus Humano 16/patogenicidade , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Oncogênicas Virais/antagonistas & inibidores , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Células RAW 264.7 , RNA-Seq , Rimantadina/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Adulto Jovem
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