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1.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201353

RESUMO

We identified the microRNA (miRNA) expression signature of head and neck squamous cell carcinoma (HNSCC) tissues by RNA sequencing, in which 168 miRNAs were significantly upregulated, including both strands of the miR-31 duplex (miR-31-5p and miR-31-3p). The aims of this study were to identify networks of tumor suppressor genes regulated by miR-31-5p and miR-31-3p in HNSCC cells. Our functional assays showed that inhibition of miR-31-5p and miR-31-3p attenuated cancer cell malignant phenotypes (cell proliferation, migration, and invasion), suggesting that they had oncogenic potential in HNSCC cells. Our in silico analysis revealed 146 genes regulated by miR-31 in HNSCC cells. Among these targets, the low expression of seven genes (miR-31-5p targets: CACNB2 and IL34; miR-31-3p targets: CGNL1, CNTN3, GAS7, HOPX, and PBX1) was closely associated with poor prognosis in HNSCC. According to multivariate Cox regression analyses, the expression levels of five of those genes (CACNB2: p = 0.0189; IL34: p = 0.0425; CGNL1: p = 0.0014; CNTN3: p = 0.0304; and GAS7: p = 0.0412) were independent prognostic factors in patients with HNSCC. Our miRNA signature and miRNA-based approach will provide new insights into the molecular pathogenesis of HNSCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Neoplasias de Cabeça e Pescoço/patologia , MicroRNAs/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Biomarcadores Tumorais/genética , Proliferação de Células , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas
2.
World J Surg Oncol ; 19(1): 210, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34256803

RESUMO

OBJECTIVE: This meta-analysis was implemented to evaluate the association between hypoxia-inducible factor-1α (HIF-1α) C1772T/G1790A polymorphisms and susceptibility to head and neck cancer (HNC). MATERIAL AND METHODS: This meta-analysis has been registered on PROSPERO platform ( CRD42021257309 ). The PubMed, Embase and Web of Science databases were searched to retrieve eligible published papers. STATA software was used to calculate the pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to assess the correlation strength. RESULTS: Our results demonstrated that the HIF-1α C1772T polymorphism was significantly related to an increased HNC risk (OR = 2.27, 95% CI = 1.17-4.42 for the homozygous model; OR = 11.53, 95% CI = 1.11-120.4 for the recessive model), especially in Caucasians (OR = 2.16, 95% CI = 1.09-4.27 for the homozygous model; OR = 2.28, 95% CI = 1.15-5.51 for the recessive model). Similarly, a remarkable correlation was discovered between the G1790A polymorphism and HNC risk (OR = 72.11, 95% CI = 2.08-2502.4 for the homozygous model; OR = 58.05, 95% CI = 1.70-1985.77 for the recessive model). Moreover, in the subgroup analysis by source of controls, a statistically significant correlation was discovered in the population-based (PB) subgroup (OR = 9.43, 95% CI = 1.20-73.9 for allelic model; OR = 72.11, 95% CI = 2.08-2502.4 for the homozygous model; OR = 3.22, 95% CI = 1.28-8.08 for the heterozygous model; OR = 7.83, 95% CI = 1.48-41.37 for the dominant model; OR = 58.05, 95% CI = 1.70-1985.8 for the recessive model) but not in the hospital-based (HB) subgroup. CONCLUSION: Our study found that both HIF-1α C1772T and G1790A polymorphisms might be a higher risk of HNC, especially in the Caucasian group with the C1772T polymorphism.


Assuntos
Neoplasias de Cabeça e Pescoço , Subunidade alfa do Fator 1 Induzível por Hipóxia , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Polimorfismo de Nucleotídeo Único , Prognóstico
3.
Anticancer Res ; 41(7): 3363-3370, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230132

RESUMO

BACKGROUND/AIM: The mechanisms through which cetuximab (cMab) coadministration with paclitaxel (PTX) enhances antitumor efficacy remain unclear. We examined the mechanism of the antitumor enhancing effect of cMab by determining changes in gene expression in the PI3K-AKT pathway. MATERIALS AND METHODS: Eight human oral squamous cell carcinoma (OSCC) cell lines were cultured three-dimensionally and exposed to PTX + cMab. The expression levels of PTEN mRNA in OSCC cell lines after anticancer drug treatment were assessed using real-time PCR. PTEN mRNA expression levels were also confirmed after administration of PTX + cMab in vivo. Western blot analysis was used to confirm the results at the protein level. RESULTS: PTEN mRNA and protein expression were significantly increased only in the cell lines with high sensitivity to PTX + cMab, and similar results were observed in vivo. CONCLUSION: PTEN activation may enhance the antitumor effect of PTX + cMab.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , PTEN Fosfo-Hidrolase/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Cetuximab/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Paclitaxel/farmacologia , Fosfatidilinositol 3-Quinases/genética
4.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204834

RESUMO

In head and neck cancers, the effectiveness of cisplatin (CisPt) treatment is limited by its toxicity, especially when higher doses are necessary, and the possible occurrence of cisplatin resistance. This study evaluated the effects of resveratrol (RSV) on the expression of different genes involved in the response of human tumor cells (FaDu, PE/CA-PJ49) to cisplatin therapy. Our results revealed that RSV induced apoptosis amplification in both FaDu and PE/CA-PJ49 cells and modulated the expression of specific genes differently than in normal HaCaT cells. In FaDu cells, combined CisPt + RSV treatment induced an increase in apoptosis, which was associated with an increase in c-MYC and TP53 and a decrease in BCL-2 expression. While CisPt + RSV treatment induced apoptosis in PE/CA-PJ49 cells by inhibition of BCL-2 associated with high levels of MDM-2 and subsequently led to inhibition of TP53 gene expression. Decreased c-MYC expression in PE/CA-PJ49 treated with CisPt + RSV was accompanied by cell cycle blockage in G0/G1 phase. In conclusion, RSV influences tumor cell response to CisPt by inducing apoptosis and modulating gene expression. In addition, in normal HaCaT cells, RSV was able to reduce the harmful effects of CisPt.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/patologia , Resveratrol/farmacologia , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/genética , Humanos , Concentração Inibidora 50
5.
J Int Med Res ; 49(7): 3000605211022534, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34232797

RESUMO

OBJECTIVES: Human papillomavirus (HPV) is a risk factor for head and neck squamous cell carcinoma (HNSCC), which is currently increasing worldwide. We evaluated the prevalence of HPV DNA and p16 expression in HNSCC patients age <45 years compared with patients aged ≥45 years. METHODS: Thirty-nine patients aged <45 years who presented at Besançon University Hospital with HNSCC since 2005 were included in this retrospective study. HPV DNA was detected by HPV genotyping and p16 expression was determined by immunohistochemistry using paraffin-embedded tissues. A matched-group of 38 patients aged ≥45 years from Besançon University Hospital was included. RESULTS: The overall prevalence of HPV infection was 11.7%. HPV16 was the only genotype detected in 4/39 and 5/38 patients, and p16 was expressed in 6/39 and 4/38 patients aged <45 years and ≥45 years, respectively. CONCLUSIONS: HPV-positivity and p16 expression were similar in both age groups. The results suggest that p16 immunohistochemistry may provide a prognosis biomarker for all HNSCCs, not only oropharyngeal cancers, and this should be addressed in large clinical trials.


Assuntos
Alphapapillomavirus , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Alphapapillomavirus/genética , Carcinoma de Células Escamosas/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , DNA Viral/genética , Neoplasias de Cabeça e Pescoço/genética , Humanos , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/genética , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
6.
J Biol Regul Homeost Agents ; 35(3): 975-986, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34159769

RESUMO

This study aimed to screen the key immune-related genes (IRGs) in head and neck squamous cell carcinoma (HNSC) and construct the IRGs-related prognostic model to predict the overall survival (OS) of patients with HNSC. The RNA-seq data and clinical data were downloaded from The Cancer Genome Atlas database, and IRGs were obtained from the Immunology Database and Analysis Portal. Differentially expressed genes (DEGs) between HNSC and normal samples were identified, followed by integration with IRGs to screen differentially expressed IRGs. After univariate and multivariate proportional hazard regression analyses, an IRG-based risk model was constructed. Meanwhile, data chip of GSE65858 as the validation set to assess the predicted performance of established model. Next, univariate and multivariate Cox regression analyses were performed to identify the independent prognostic factor of HNSC, and the Nomogram model was developed to predict patient outcome. Furthermore, the correlation between immune cell infiltration and risk score was analyzed. A total of 65 differently expressed IRGs associated with prognosis of HNSC were screened, and finally a 26-gene IRG signature was identified to construct a prognostic prediction model. The AUC of ROC curve was 0.750. Survival analysis showed that patients in the high-risk group had a worse prognosis. Independent prognostic analysis showed that risk score could be considered as an independent predictor for HNSC prognosis. Nomogram assessment showed that the model had high reliability for predicting the survival of patients with HNSC in 1, 2, 3 years. Ultimately, the abundance of B cells and CD4+ T cell infiltration in HNSC showed negative correlations with risk score. Our IRG-based prognostic risk model may be used to estimate the prognosis of HNSC patients.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço , Biomarcadores Tumorais/genética , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Prognóstico , Reprodutibilidade dos Testes
7.
Mutat Res ; 787: 108358, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34083052

RESUMO

A systematic review and a meta-analysis were performed on 19 studies on head and neck cancer (HNC) and 21 studies on breast cancer (BC) to evaluate the application of micronucleus (MN) assay as a predictive and prognostic test for cancer risk. In these studies the MN test was applied in peripheral lymphocytes and buccal cells of patients and healthy subjects with family history of cancer. The meta-analysis on MN applied in buccal cells of HNC patients was performed on two subgroups of studies. A significant increase of MN frequency in patients compared to healthy controls was observed for the subgroup on oral cancer (243 cases/370 controls, meta-MR = 4.71 95 %CI:2.75-8.06) and HNC (204 patients/163 controls metaMR=2.28 95 %CI:2.02-2.58). A metaMR = 3.27 (95 %CI:1.41-7.59) was obtained for MN applied in peripheral lymphocytes on HNC (160 cases/160 controls). For BC, the analysis of MN in peripheral lymphocytes showed significantly higher values in patients (n = 761) than in controls (n = 788) (meta-MR1.90 95 % CI:1.44-2.49). No statistically significant increase of baseline MN was detected in studies on groups of healthy subjects with BC family history (n = 224) or with BRCA1/2 mutations (n = 101) with respect to the controls. After ex-vivo challenge with ionizing radiation, the meta-analysis revealed a slightly statistically significant increase in MN only in BC patients (n = 614) compared to controls (n = 622)(meta-MR = 1.11 95 %CI:1.02-1.21); no increase was observed in healthy subjects with BC family history carrying or not BRCA1/2 mutations. Significant difference between BC patients (n = 183) and controls (n = 165) was observed by the meta-analysis of data on MN in buccal cells (MR = 3.89 95 %CI:1.54-9.78). The MN assay in buccal cells has some perspective of clinical application in HNC.


Assuntos
Neoplasias da Mama/genética , Neoplasias de Cabeça e Pescoço/genética , Testes para Micronúcleos/métodos , Neoplasias Bucais/genética , Feminino , Humanos , Masculino
8.
Nat Commun ; 12(1): 3974, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172737

RESUMO

Cancer stem cells (CSCs) play a critical role in invasive growth and metastasis of human head and neck squamous cell carcinoma (HNSCC). Although significant progress has been made in understanding the self-renewal and pro-tumorigenic potentials of CSCs, a key challenge remains on how to eliminate CSCs and halt metastasis effectively. Here we show that super-enhancers (SEs) play a critical role in the transcription of cancer stemness genes as well as pro-metastatic genes, thereby controlling their tumorigenic potential and metastasis. Mechanistically, we find that bromodomain-containing protein 4 (BRD4) recruits Mediators and NF-κB p65 to form SEs at cancer stemness genes such as TP63, MET and FOSL1, in addition to oncogenic transcripts. In vivo lineage tracing reveals that disrupting SEs by BET inhibitors potently inhibited CSC self-renewal and eliminated CSCs in addition to elimination of proliferating non-stem tumor cells in a mouse model of HNSCC. Moreover, disrupting SEs also inhibits the invasive growth and lymph node metastasis of human CSCs isolated from human HNSCC. Taken together, our results suggest that targeting SEs may serve as an effective therapy for HNSCC by eliminating CSCs.


Assuntos
Elementos Facilitadores Genéticos , Neoplasias de Cabeça e Pescoço/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Antineoplásicos/farmacologia , Azepinas/farmacologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Metástase Linfática/tratamento farmacológico , Metástase Linfática/prevenção & controle , Subunidade 1 do Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/metabolismo , Camundongos Endogâmicos C57BL , Camundongos SCID , NF-kappa B/genética , Células-Tronco Neoplásicas/patologia , Complexo Repressor Polycomb 1/antagonistas & inibidores , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Triazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067112

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease arising from the mucosa of the upper aerodigestive tract. Despite multimodality treatments approximately half of all patients with locally advanced disease relapse and the prognosis of patients with recurrent or metastatic HNSCC is dismal. The introduction of checkpoint inhibitors improved the treatment options for these patients and pembrolizumab alone or in combination with a platinum and fluorouracil is now the standard of care for first-line therapy. However, approximately only one third of unselected patients respond to this combination and the response rate to checkpoint inhibitors alone is even lower. This shows that there is an urgent need to improve prognostication and prediction of treatment benefits in patients with HNSCC. In this review, we summarize the most relevant risk factors in the field and discuss their roles and limitations. The human papilloma virus (HPV) status for patients with oropharyngeal cancer and the combined positive score are the only biomarkers consistently used in clinical routine. Other factors, such as the tumor mutational burden and the immune microenvironment have been highly studied and are promising but need validation in prospective trials.


Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Antígeno B7-H1/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Mutação/genética , Estadiamento de Neoplasias , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Tabaco
10.
Anticancer Res ; 41(6): 2773-2779, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083267

RESUMO

Head and neck carcinoma (HNC) comprises a variety of pathological entities. Among them, squamous cell carcinoma (SCC) is histo-pathologically prominent. Specific malignancies, such as nasopharyngeal carcinoma (NPC) arise also from the same anatomical region. In all of them, genomic instability (GI) is implicated not only in the early stages of epithelial malignant transformation, but also in the aggressiveness of the corresponding phenotypes. Among the molecules that are frequently deregulated in solid malignancies including HNCs, topoisomerases (Topo) are of increased significance due to their involvement in DNA topological, structural, and functional stability. The main members are Topo I (20q11), Topo II alpha (17q21) and Topo IIb (3p24). In the current article, we describe the mechanisms of Topo I and Topo IIa deregulation leading to GI in a variety of HNCs. Furthermore, novel data regarding the corresponding targeted therapeutic strategies are presented.


Assuntos
DNA Topoisomerases Tipo I/metabolismo , Instabilidade Genômica , Neoplasias de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia , DNA Topoisomerases Tipo I/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
11.
Magy Onkol ; 65(2): 188-195, 2021 06 03.
Artigo em Húngaro | MEDLINE | ID: mdl-34081766

RESUMO

Head and neck squamous cell carcinomas (HNSCC) take many lifes worldwide. Patients with recurrent/metastatic disease receive combination chemotherapy containing anti-EGFR antibody cetuximab. However, resistance often hurdles therapy. The mechanism is yet to unveil, although EGFR extracellular alterations and activity of c-Met signaling were accused. We investigated the effects of EGFR-vIII and EGFR-R521K on cetuximab efficacy in HNSCC in cellular, xenograft, and clinical setup. Furthermore, we investigated the efficacy of c-Met inhibition in HNSCC in vitro and in vivo. We showed that EGFR-vIII is very rare in HNSCC, while the common R521K polymorphism abolishes antibody-dependent cellular cytotoxicity and in vivo antitumor effect of cetuximab. This selectivity was not reflected in immunophenotype or survival data of HNSCC patients, suggesting a more complex mechanism behind. Interestingly, c-Met inhibitor SU11274 was more effective in cetuximab-resistant, EGFR R521K heterozygous cells and xenografts, raising the possible importance of simultaneous targeting of the two receptors.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Cetuximab/farmacologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Nat Commun ; 12(1): 3349, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099645

RESUMO

Current immunotherapy paradigms aim to reinvigorate CD8+ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied. Here, we demonstrate that in head and neck squamous cell carcinoma (HNSCC) caused by human papillomavirus infection (HPV+), patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with tertiary lymphoid structures (TLS) with GCs, both of which correlate with favorable outcome. GC TIL-Bs in HPV+ HNSCC are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. Semaphorin 4a expression is enhanced on GC TIL-Bs present in TLS of HPV+ HNSCC and during the differentiation of TIL-Bs. Our study suggests that therapeutics to enhance TIL-B responses in HNSCC should be prioritized in future studies to determine if they can complement current T cell mediated immunotherapies.


Assuntos
Linfócitos B/imunologia , Neoplasias de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Estruturas Linfoides Terciárias/metabolismo , Análise de Variância , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos/imunologia , Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Imunoterapia/métodos , Infecções por Papillomavirus , Semaforinas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Análise de Sobrevida , Linfócitos T
13.
Life Sci ; 280: 119705, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34111459

RESUMO

BACKGROUND: Bcl-xL is an anti-apoptotic molecule, but its role in the progression and recurrent/ drug-resistant oral squamous cell carcinoma (OSCC) is poorly understood. MATERIALS AND METHODS: A total of one hundred twenty-five human OSCC tissue specimens including twenty-nine adjacent normals (AN), sixty-nine primary tumors (PT), twenty-seven recurrent chemoradiation resistance (RCRT) samples, and oral tongue SCC derived cisplatin-resistant (CisR SCC-4/-9) cells were used, for this study. Protein/mRNA expression levels of Bcl-xL and its regulation by ERK1/2, Stat-3, p53, NFκB, AP-1 (components: c-Jun, c-Fos, and Fra-2) molecules, and cell viability were measured by immunohistochemistry, Western blot, RT-PCR, and MTT analysis. Further, the individual and synergistic effects of Fra-2 (siRNA) and nimbolide were tested in CisR SCC-4/-9 cells. RESULTS: Progressive increase of Bcl-xL expression and its transcriptional-deregulation was observed with OSCC progression and resistance. Among all the possible upstream regulators of Bcl-xL, such as ERK1/2, Stat-3, p53, AP-1, and NFκB, the TF AP-1 (r = 0.644, p = 0.0001) showed maximum association with Bcl-xL mRNA expression. Though differential expression of AP-1 components were detected in OSCC specimens, with more striking positive-correction of c-Jun (r = 0.381, p = 0.049), c-Fos (r = 0.139, p = 0.488, ns) and Fra-2 (r = 0.664, p = 0.0001) with Bcl-xL expression observed stronger in RCRT tumor subgroup. Further, knockdown of Fra-2 and the application of plant-based phytochemical nimbolide decreased Bcl-xL expression and induced apoptosis in CisR SCC-4/-9 cells. CONCLUSION: Collectively, we have demonstrated the role of Bcl-xL and AP-1 (Fra-2), causing OSCC progression and cisplatin resistance. Targeting Bcl-xL upstream pathway along with the application of nimbolide might be beneficial in eliminating drug-resistant OSCC.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias Bucais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Proteína bcl-X/genética , Adulto , Idoso , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico
14.
Comput Biol Med ; 134: 104473, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34034219

RESUMO

Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide, which accounts for approximately 6% of all cases and is responsible for an estimated 2% of all cancer deaths. Despite progress in the treatment of squamous cell carcinomas, survival rates remain low. It is a fact that epigenetic modifications have numerous associations with biological processes and complex diseases such as cancer. Hence, a more systematic approach is needed to provide potential screening targets and have an effective therapy method. This study developed a workflow to analyze HM450 methylation arrays with mRNA expression profiles that identified novel signatures of epigenetic regulators for tumor progression. We identified differentially expressed genes and differentially methylated regions and the correlation between associated genes to identify epigenetic modifications underlying regulation roles. We have taken the differentiation direction of expressions into account during the integration of gene expression and DNA methylation modification to detect epigenetic regulators of core genes of tumor-stage progression. Enrichment analysis of selected key genes provides better insight into their functionality. Thus, we have investigated gene copy number alteration and mutations to filter differentially expressed genes, including some members of the fibroblast growth factor family and cyclin-dependent kinase inhibitor family with other potential known regulators. Our analysis has revealed the list of 61 commercial methylation probes positively correlated with 31 differentially expressed genes, which can be associated with HNSC metastasis stages. Most of these genes have already reported potential epigenetic regulators, and their role in cancer progression was studied. We suggest these selected probes of DNA methylation as potential targets of the epigenetic regulators in revealed genes that have displayed significant genetic and epigenetic modification behavior during cancer stage progression and tumor metastasis.


Assuntos
Metilação de DNA , Neoplasias de Cabeça e Pescoço , Metilação de DNA/genética , Epigênese Genética/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Humanos , Regiões Promotoras Genéticas , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
15.
Curr Protoc ; 1(5): e146, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34033698

RESUMO

Human papillomaviruses (HPVs), specifically high-risk HPVs, are responsible for up to 3% of all cancers in women and up to 2% of all cancers in men. They have been identified as the etiological agent of cervical cancer and have been increasingly found to be the driver behind head and neck cancers of the oropharynx. A system in which we can simultaneously observe transcriptional changes to both a host's tumor microenvironment and its associated oncogenic driver (e.g., HPV) would be highly valuable for understanding HPV's role in tumorigenesis. This article describes a detailed methodology for utilizing high-throughput RNA analysis to study viral transcription in formalin-fixed, paraffin-embedded clinical tumor samples. Although our lab utilizes these methods for the study of head and neck cancer, the principles contained within are widely applicable to all fields of HPV study. © 2021 Wiley Periodicals LLC. Basic Protocol: HPV16 transcript analysis using NanoString Support Protocol 1: Preparation of RNA from formalin-fixed, paraffin-embedded slides Support Protocol 2: Preparation of RNA from cell lysates Support Protocol 3: Fluorometric RNA concentration and RNA integrity analysis Support Protocol 4: Determination of input RNA based on DV300 calculation.


Assuntos
Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/virologia , Sequenciamento de Nucleotídeos em Larga Escala , Papillomavirus Humano 16/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Transcrição Genética , Microambiente Tumoral/genética , Fluorometria , Formaldeído , Regulação Viral da Expressão Gênica , Humanos , Inclusão em Parafina , RNA Neoplásico/genética , RNA Neoplásico/isolamento & purificação , Robótica , Fixação de Tecidos
16.
J Transl Med ; 19(1): 212, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001187

RESUMO

BACKGROUND: Optimizing the therapeutic ratio for radiation therapy (RT) in head and neck squamous cell carcinoma (HNSCC) is uniquely challenging owing to high rates of early and late toxicity involving nearby organs at risk. These toxicities have a profound impact on treatment compliance and quality of life. Emerging evidence suggests that RT dose alone cannot fully account for the variable severity of RT-related adverse events (rtAEs) observed in HNSCC patients. Next-generation sequencing has become an increasingly valuable tool with widespread use in the oncology field and is being robustly explored for predicting rtAEs beyond dosimetric data. METHODS: Patients who had Foundation Medicine sequencing data and received RT for primary or locally recurrent HNSCC were selected for this study. Early and late toxicity data were collected and reported based on Common Terminology Criteria for Adverse Events version 5.0. Dosimetric parameters were collected for pertinent structures. RESULTS: A total of HNSCC 37 patients were analyzed in this study. Genetic alterations in BRCA2, ERBB3, NOTCH1 and CCND1 were all associated with higher mean grade of toxicity with BRCA2 alteration implicated in all toxicity parameters evaluated including mucositis, early dysphagia, xerostomia and to a lesser extent, late dysphagia. Interestingly, patients who exhibited alterations in both BRCA2 and ERBB3 experienced a twofold or greater increase in early dysphagia, early xerostomia and late dysphagia compared to ERBB3 alteration alone. Furthermore, several gene alterations were associated with improved toxicity outcomes. Within an RT supersensitive patient subset, alterations were found in TNFAIP3, HNF1A, SPTA1 and CASP8. All of these alterations were not found in the RT insensitive patient subset. We found 17 gene alterations in the RT insensitive patient subset that were not found in the RT supersensitive patient subset. CONCLUSION: Despite consistent RT dosimetric parameters, patients with HNSCC experience heterogeneous patterns of rtAEs. Identifying factors associated with toxicity outcomes offers a new avenue for personalized precision RT therapy and prophylactic management. Here, next-generation sequencing in a population of HNSCC patients correlates several genetic alterations with severity of rtAEs. Further analysis is urgently needed to identify genetic patterns associated with rtAEs in order to reduce harmful outcomes in this challenging population.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Recidiva Local de Neoplasia , Qualidade de Vida , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
17.
Aging (Albany NY) ; 13(8): 11507-11527, 2021 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-33867351

RESUMO

Head and neck squamous cell carcinoma (HNSCC), the most frequent subtype of head and neck cancer, continues to have a poor prognosis with no improvement. The TNM stage is not satisfactory for individualized prognostic assessment and it does not predict response to therapy. In the present study, we downloaded the gene expression profiles from TCGA database to establish a training set and GEO database for a validation set. In the training set, we developed an 10 immune-related genes signature which had superior predictive value compared with TNM stage. A nomogram including clinical characteristics was also constructed for accurate prediction. Furthermore, it was determined that our prognostic signature might act as an independent factor for predicting the survival of HNSCC patients. As for the immune microenvironment, our results showed higher immune checkpoint expression (CLTA-4 and PD-1) in low-risk group which might reflect a positive immunotherapy response. Thus, our signature not only provided a promising biomarker for survival prediction, but might be evaluated as an indicator for personalized immunotherapy in patients with HNSCC.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias de Cabeça e Pescoço/mortalidade , Nomogramas , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Medicina de Precisão/métodos , Valor Preditivo dos Testes , Curva ROC , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Microambiente Tumoral/genética
18.
Nat Commun ; 12(1): 2383, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888713

RESUMO

Immune checkpoint blockade (ICB) therapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, but <20% of patients achieve durable responses. Persistent activation of the PI3K/AKT/mTOR signaling circuitry represents a key oncogenic driver in HNSCC; however, the potential immunosuppressive effects of PI3K/AKT/mTOR inhibitors may limit the benefit of their combination with ICB. Here we employ an unbiased kinome-wide siRNA screen to reveal that HER3, is essential for the proliferation of most HNSCC cells that do not harbor PIK3CA mutations. Indeed, we find that persistent tyrosine phosphorylation of HER3 and PI3K recruitment underlies aberrant PI3K/AKT/mTOR signaling in PIK3CA wild type HNSCCs. Remarkably, antibody-mediated HER3 blockade exerts a potent anti-tumor effect by suppressing HER3-PI3K-AKT-mTOR oncogenic signaling and concomitantly reversing the immune suppressive tumor microenvironment. Ultimately, we show that HER3 inhibition and PD-1 blockade may provide a multimodal precision immunotherapeutic approach for PIK3CA wild type HNSCC, aimed at achieving durable cancer remission.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor ErbB-3/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Camundongos , Mutação , Medicina de Precisão/métodos , Receptor de Morte Celular Programada 1/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , 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/patologia , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Cancer Sci ; 112(6): 2325-2334, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33811778

RESUMO

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway plays a vital role in cell proliferation, apoptosis, metabolism, and angiogenesis in various human cancers, including head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to clarify the role of AKT, which is a major downstream effector of the PI3K-AKT-mTOR pathway, in HNSCC. We first investigated the mRNA expression of AKT isoforms using RNA-sequencing data from The Cancer Genome Atlas database. We observed a specific elevation of AKT3 expression in HNSCC tissues when compared with that in normal tissues. Furthermore, AKT3 expression correlated with genes related to the immunosuppressive microenvironment more than the other AKT isoforms and PIK3CA. Accordingly, we focused on AKT3 and performed a knockdown approach using an HNSCC cell line. AKT3 knockdown cells exhibited impaired proliferation, a shift in the cell cycle from G2/M to G1/G0 phase, an increase in apoptotic cells, and downregulation of gene expression related to immunosuppression, as well as the knockdown of its upstream regulator PIK3CA. We also performed immunohistochemistry for both AKT3 and PIK3CA using surgical specimens from 72 patients with HNSCC. AKT3 expression in tumor cells correlated with immune cell infiltration and unfavorable prognosis when compared with PIK3CA. These findings suggested that AKT3 expression is a potential biomarker for predicting the immunoreactivity and prognosis of HNSCC. Furthermore, the isoform-specific inhibition of AKT3 could be developed as a novel cancer therapy that efficiently suppresses the PI3K-AKT-mTOR pathway.


Assuntos
Neoplasias de Cabeça e Pescoço/cirurgia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Análise de Sequência de RNA/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Regulação para Cima , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Análise de Sobrevida , Microambiente Tumoral
20.
Life Sci ; 278: 119541, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33930368

RESUMO

AIMS: In vitro and in vivo studies suggest that the mu-opioid receptor (MOR) is involved in tumorigenesis, and metastasis in cancer. In humans, the use of MOR agonists (opioids) is associated with head and neck squamous cell carcinoma (HNSCC) progression. In the present study, we aimed to examine the role of MOR activation in MOR (+) HNSCC. MAIN METHODS: FaDu, MDA686Tu and UMSCC47 cell lines were used in in vitro and in vivo experiments. Cells and animals were treated with a highly selective MOR agonist DAMGO, [D-Ala (2), Me Phe (4), Glycol (5)]-enkephalin] or saline 0.9%. KEY FINDINGS: MOR activation significantly increased the proliferation, colony formation, invasion, and migration of FaDu and MDA6868Tu cells and promoted tumor growth in vivo. SIGNIFICANCE: These findings suggest that MOR is implicated in tumorigenesis of HNSCC. Overall, our findings identify that MOR could be used as a potential therapeutic target in patients with MOR (+) HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço/metabolismo , Receptores Opioides mu/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Nus , Receptores Opioides mu/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
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