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1.
Anticancer Res ; 41(7): 3439-3448, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230139

RESUMO

BACKGROUND/AIM: The role of immune cells and PD-L1 in cutaneous squamous carcinogenesis is unclear. This study examines T-cell populations, Langerhans cells (LCs) and PD-L1 in invasive squamous cell carcinoma (inSCC), adjacent precursors and normal skin (NS) to investigate their participation in tumorigenesis. MATERIALS AND METHODS: Cases of cutaneous inSCC with adjacent precursors (n=125) were selected. In situ SCC (isSCC) and actinic keratosis (AK) were observed in 53 and 123 cases, respectively, whereas NS was present in 123 lesions. Immunohistochemistry was performed for CD3, CD8, Foxp3, CD1a and PD-L1. RESULTS: T-cells, LCs and PD-L1 gradually increase during the evolution from AK to isSCC and inSCC, with statistical significance between all lesions, except for CD3+ and CD8+ cells between isSCC and inSCC. Epithelial PD-L1 expression correlates with tumor diameter and thickness. CONCLUSION: The progressive increase of T-cells, LCs and PD-L1 in cutaneous squamous carcinogenesis provides rationale for immunotherapy and identification of predictive biomarkers.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/metabolismo , Células de Langerhans/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Subpopulações de Linfócitos T/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Complexo CD3/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Células de Langerhans/imunologia , Células de Langerhans/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/patologia , Subpopulações de Linfócitos T/imunologia , Microambiente Tumoral/imunologia
2.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209172

RESUMO

Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with dual pathogenesis, Human papillomavirus (HPV)-associated and HPV-independent, with a poorly explored molecular landscape. We aimed to summarize the findings of the series analyzing molecular hallmarks of this neoplasm. In January 2021, we conducted a comprehensive literature search using Pubmed Medline and Scopus to identify publications focused on genomic profiling of VSCC. Observational studies, including both prospective and retrospective designs, evaluating molecular alterations in VSCC were deemed eligible. A total of 14 studies analyzing 749 VSCC were identified. The study series were heterogeneous in HPV testing and sequencing strategies, included small sets of tumors and cancer genes, and commonly lacked survival analysis. Only one extensive targeted next-generation sequencing-based study comprised a large cohort of 280 VSCC. The mutated genes, their number, and frequencies were highly variable between the series. Overall, TP53 and CDKN2A, followed by PIK3CA, HRAS, and PTEN, were the most frequently studied and mutated genes. Mutations involved in the PI3K/AKT/mTOR pathway, including TP53, HRAS, KRAS, and PIK3CA, have been consistently reported across the studies. However, the role of individual mutations or pathways in the development of VSCC remains unclear. In conclusion, heterogeneity and the small sample size of available molecular series contribute to a limited view of the molecular landscape of VSCC. Large-scale genome- or exome-wide studies with robust HPV testing are necessary to improve the molecular characterization of VSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Mutação , Proteínas de Neoplasias/genética , Neoplasias Vulvares/genética , Carcinoma de Células Escamosas/metabolismo , Feminino , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias Vulvares/metabolismo
3.
J Cardiothorac Surg ; 16(1): 194, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233689

RESUMO

OBJECTIVE: C-erbB-2 has been confirmed to be an oncogene that participates in cell growth, differentiation and division of tumors. We are wondered if its silenced expression can exert an anti-tumor effect. Therefore, this study is conducted to investigate the mechanism of C-erbB-2 silencing and IGF-1 pathway on esophageal carcinoma (EC) cell biological behaviors. METHODS: The objects of study were 84 EC patients from Heping Hospital Affiliated to Changzhi Medical College, with the collection of EC tissue and adjacent normal tissue (> 5 cm away from cancer tissue). C-erbB-2 protein expression in EC tissues was detected by immunohistochemistry. Human EC cell line Eca-109 was purchased from Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. Based on different transfection protocols, EC cells with logarithmic growth phase of 3-5 passages were divided into blank control group, oe-C-erbB-2 NC group, siRNA C-erbB-2 NC group, oe-C-erbB-2 group, siRNA C-erbB-2 group, OSI-906 group, Rg5 group, Rg5 + siRNA C-erbB-2 NC group and Rg5 + siRNA C-erbB-2 group. Cell proliferation was detected by MTT assay; cell cycle distribution and apoptosis by flow cytometry; C-erbB-2, IGF-1, IGF-1R and Akt mRNA and protein expressions by qRT-PCR and western blot; and cell invasion and migration by Transwell assay and scratch test. Tumor growth was observed in male BALB/c nude mice (Shanghai Experimental Animal Center) based on Eca109 cell implantation, raising, and measurement. RESULTS: C-erbB-2, IGF-1, IGF-1R and Akt expression were higher in EC tissues than those in adjacent tissues (all P < 0.05). Compared with blank control group, both si-C-erbB-2 and OSI-906 groups had decreased IGF-1, IGF-1R and Akt mRNA and protein expressions, decreased cell proliferation, migration and invasion, prolonged G0/G1 phase, shortened S phase, increased cell apoptosis, and inhibited tumor growth (all P < 0.05); while opposite trends were detected in C-erbB-2 vector and Rg5 groups (all P < 0.05), without statistical differences in siRNA C-erbB-2 + Rg5 group (all P > 0.05). CONCLUSION: Silencing C-erbB-2 expression may inhibit EC cell proliferation, promote cell apoptosis and block cell cycle progression by inhibiting IGF-1 pathway activation. The beneficial effect of silencing C-erbB-2 expression can be reversed by promoting the activation of IGF-1 pathway. Findings in our study may provide potential reference for understanding the molecular mechanism of EC and supply possible axis for preventing the development of EC from the perspective of molecular biology.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Inativação Gênica/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Receptor ErbB-2/genética , Adulto , Idoso , Animais , Apoptose/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Transplante de Neoplasias , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor IGF Tipo 1 , Transfecção
4.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202728

RESUMO

The prognosis of patients with oral squamous carcinoma (OSCC) largely depends on the stage at diagnosis, the 5-year survival rate being approximately 30% for advanced tumors. Early diagnosis, including the detection of lesions at risk for malignant transformation, is crucial for limiting the need for extensive surgery and for improving disease-free survival. Saliva has gained popularity as a readily available source of biomarkers (including cytokines) useful for diagnosing specific oral and systemic conditions. Particularly, the close interaction between oral dysplastic/neoplastic cells and saliva makes such fluid an ideal candidate for the development of non-invasive and highly accurate diagnostic tests. The present review has been designed to answer the question: "Is there evidence to support the role of specific salivary cytokines in the diagnosis of OSCC?" We retrieved 27 observational studies satisfying the inclusion and exclusion criteria. Among the most frequent cytokines investigated as candidates for OSCC biomarkers, IL-6, IL-8, TNF-α are present at higher concentration in the saliva of OSCC patients than in healthy controls and may therefore serve as basis for the development of rapid tests for early diagnosis of oral cancer.


Assuntos
Biomarcadores , Carcinoma de Células Escamosas/metabolismo , Citocinas/metabolismo , Neoplasias Bucais/metabolismo , Saliva/metabolismo , Biomarcadores Tumorais , Carcinoma de Células Escamosas/diagnóstico , Humanos , Biópsia Líquida/métodos , Neoplasias Bucais/diagnóstico , Prognóstico
5.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065916

RESUMO

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a devastating skin blistering disease caused by mutations in the gene encoding type VII collagen (C7), leading to epidermal fragility, trauma-induced blistering, and long term, hard-to-heal wounds. Fibrosis develops rapidly in RDEB skin and contributes to both chronic wounds, which emerge after cycles of repetitive wound and scar formation, and squamous cell carcinoma-the single biggest cause of death in this patient group. The molecular pathways disrupted in a broad spectrum of fibrotic disease are also disrupted in RDEB, and squamous cell carcinomas arising in RDEB are thus far molecularly indistinct from other sub-types of aggressive squamous cell carcinoma (SCC). Collectively these data demonstrate RDEB is a model for understanding the molecular basis of both fibrosis and rapidly developing aggressive cancer. A number of studies have shown that RDEB pathogenesis is driven by a radical change in extracellular matrix (ECM) composition and increased transforming growth factor-beta (TGFß) signaling that is a direct result of C7 loss-of-function in dermal fibroblasts. However, the exact mechanism of how C7 loss results in extensive fibrosis is unclear, particularly how TGFß signaling is activated and then sustained through complex networks of cell-cell interaction not limited to the traditional fibrotic protagonist, the dermal fibroblast. Continued study of this rare disease will likely yield paradigms relevant to more common pathologies.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Colágeno Tipo VII/genética , Epidermólise Bolhosa Distrófica/complicações , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/genética , Colágeno Tipo VII/metabolismo , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/metabolismo , Matriz Extracelular/metabolismo , Fibrose , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Fator de Crescimento Transformador beta/metabolismo , Cicatrização
6.
Cancer Invest ; 39(6-7): 559-570, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34043476

RESUMO

The study evaluated whether SPP1/osteopontin (OPN) splice variants are differentially expressed in nonmelanoma skin cancer compared to normal skin. The absolute number of mRNA molecules of OPN-a predominated in normal skin and nonmelanoma skin cancer compared to OPN-b, OPN-c, and OPN-5. However, mRNAs of OPN-a, OPN-b, and OPN-c were expressed in higher levels in cutaneous squamous cell carcinomas (cSCCs) and basal cell carcinomas relative to normal skin. Additionally, OPN-5 expression was higher than OPN-b and OPN-c, and OPN-c, in normal skin and nonmelanoma skin cancer, respectively. Furthermore, we identified four OPN-5 splice variants, which were cloned and analyzed for protein expression.


Assuntos
Processamento Alternativo , Carcinoma Basocelular/genética , Carcinoma de Células Escamosas/genética , Osteopontina/metabolismo , Neoplasias Cutâneas/genética , Idoso , Idoso de 80 Anos ou mais , Carcinoma Basocelular/metabolismo , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Clonagem Molecular , Feminino , Regulação Neoplásica da Expressão Gênica , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Osteopontina/genética , Isoformas de RNA/metabolismo , Neoplasias Cutâneas/metabolismo , Regulação para Cima
7.
Tumour Biol ; 43(1): 99-113, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34024796

RESUMO

BACKGROUND: HPV-16 positivity in patients with squamous cell carcinoma of oropharynx (OPSCC) is associated with better prognosis. However, in more than 40% of HPV infected patients progression of cancer disease is observed, which indicates the presence of cancer cells resistant to therapy. Some studies suggest that there may be a subpopulation of cancer stem cells (CSCs), which simultaneously exhibit unlimited ability to self-renew and differentiate towards neoplastic cells. The relation between HPV16 infection and biomarkers of CSCs is unclear. OBJECTIVE: The aim of the study was to compare the expression of CD44, CD98, ALDH1/2 and P16 in oropharyngeal cancer patients with or without HPV16 infection, as well as to analyze the prognostic potential of selected CSCs biomarkers in these two subgroups. METHODS: The study was performed in a group of 63 patients. HPV16 infection status was analyzed by quantitative polymerase chain reaction, while CD44, CD98, ALDH1/2 and P16 expression by immunohistochemistry. In survival analysis, two endpoints were applied: overall survival (OS) and disease-free survival (DFS). RESULTS: Among 63 cancers, HPV16 infection was found in 25 tumors (39.7%), overexpression of CD44, CD98, ALDH1/2 and P16 in 43 (68.2%), 30 (47.6%), 33 (52.4%) and 27 (42.9%) cancers, respectively. In the HPV16-positive subgroup, DFS rate of 100% was observed in patients with tumors characterized by lack of CD44 overexpression and those treated with concurrent chemoradiotherapy with cisplatin (CisPt-CRT). In the HPV16-negative subgroup 100% of DFS was noticed for patients (n = 6) with P16 immunopositive tumors. In this subgroup none of the CSCs biomarkers evaluated in the study had any impact on OS or DFS. In patients with HPV16-positive oropharyngeal cancer, lack of CD44 overexpression and application of CisPt-CRT were found to be positive prognostic factors.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/mortalidade , Cisplatino/uso terapêutico , Receptores de Hialuronatos/metabolismo , Neoplasias Orofaríngeas/terapia , Infecções por Papillomavirus/complicações , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Feminino , Seguimentos , Papillomavirus Humano 16/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/virologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
8.
Nat Commun ; 12(1): 2581, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972544

RESUMO

While the potential of patient-derived organoids (PDOs) to predict patients' responses to anti-cancer treatments has been well recognized, the lengthy time and the low efficiency in establishing PDOs hamper the implementation of PDO-based drug sensitivity tests in clinics. We first adapt a mechanical sample processing method to generate lung cancer organoids (LCOs) from surgically resected and biopsy tumor tissues. The LCOs recapitulate the histological and genetic features of the parental tumors and have the potential to expand indefinitely. By employing an integrated superhydrophobic microwell array chip (InSMAR-chip), we demonstrate hundreds of LCOs, a number that can be generated from most of the samples at passage 0, are sufficient to produce clinically meaningful drug responses within a week. The results prove our one-week drug tests are in good agreement with patient-derived xenografts, genetic mutations of tumors, and clinical outcomes. The LCO model coupled with the microwell device provides a technically feasible means for predicting patient-specific drug responses in clinical settings.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Técnicas de Cultura de Células/métodos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Neoplasias Pulmonares/tratamento farmacológico , Organoides/efeitos dos fármacos , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais/instrumentação , Gefitinibe/farmacologia , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Organoides/citologia , Organoides/patologia , Preparações Farmacêuticas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Aging (Albany NY) ; 13(7): 9900-9910, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33882027

RESUMO

Long non-coding RNA (LncRNA) MNX1 antisense RNA 1(MNX1-AS1) is associated with the pathology of numerous cancers. But, the role and underlying pathways of MNX1-AS1 in the regulation of laryngeal squamous cell carcinoma (LSCC) is not known. We demonstrated remarkably elevated levels of MNX1-AS1 in the LSCC tissues, which was correlated with poor disease prognosis. Moreover, MNX1-AS1-silencing strongly suppressed LSCC cell proliferation, migration, and invasion. We also demonstrated that MNX1-AS1 sequesters that activity of miR-370, thereby releasing Forkhead Box ml (FoxM1) from the inhibitory actions of MNX1-AS1. Furthermore, the positive correlation of MNX1-AS1 and FoxM1 as well as the converse correlation between miR-370 and MNX1-AS1 (or FoxM1) were revealed in LSCC tissues using experiments. Based on rescue assays, FoxM1 overexpression or miR-370 downregulation partially recovered the inhibitory effect of MNX1-AS1 silencing on LSCC cells. Moreover, knockdown of MNX1-AS1 retarded tumor growth in nude mice model. In summary, these findings verified that MNX1-AS1 modulated LSCC progression by competitively binding with miR-370 to regulate FoxM1.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Proteína Forkhead Box M1/metabolismo , Neoplasias Laríngeas/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Proteína Forkhead Box M1/genética , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patologia , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , RNA Longo não Codificante/genética
10.
Int J Mol Sci ; 22(7)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918312

RESUMO

Disulfiram (DSF), an irreversible aldehyde dehydrogenase inhibitor, is being used in anticancer therapy, as its effects in humans are known and less adverse than conventional chemotherapy. We explored the potential mechanism behind the cytotoxicity of DSF-Cu+/Cu2+ complexes in oral epidermoid carcinoma meng-1 (OECM-1) and human gingival epithelial Smulow-Glickman (SG) cells. Exposure to CuCl2 or CuCl slightly but concentration-dependently decreased cell viability, while DSF-Cu+/Cu2+ induced cell death in OECM-1 cells, but not SG cells. DSF-Cu+/Cu2+ also increased the subG1 population and decreased the G1, S, and G2/M populations in OECM-1 cells, but not SG cells, and suppressed cell proliferation in both OECM-1 and SG cells. ALDH enzyme activity was inhibited by CuCl and DSF-Cu+/Cu2+ in SG cells, but not OECM-1 cells. ROS levels and cellular senescence were increased in DSF-Cu+/Cu2+-treated OECM-1 cells, whereas they were suppressed in SG cells. DSF-Cu+/Cu2+ induced mitochondrial fission in OECM-1 cells and reduced mitochondrial membrane potential. CuCl2 increased but DSF- Cu2+ impaired oxygen consumption rates and extracellular acidification rates in OECM-1 cells. CuCl2 stabilized HIF-1α expression under normoxia in OECM-1 cells, and complex with DSF enhanced that effect. Levels of c-Myc protein and its phosphorylation at Tyr58 and Ser62 were increased, while levels of the N-terminal truncated form (Myc-nick) were decreased in DSF-Cu+/Cu2-treated OECM-1 cells. These effects were all suppressed by pretreatment with the ROS scavenger NAC. Overexpression of c-Myc failed to induce HIF-1α expression. These findings provide novel insight into the potential application of DSF-CuCl2 complex as a repurposed agent for OSCC cancer therapy.


Assuntos
Inibidores de Acetaldeído Desidrogenases/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Cobre/uso terapêutico , Dissulfiram/uso terapêutico , Neoplasias Bucais/tratamento farmacológico , Inibidores de Acetaldeído Desidrogenases/química , Inibidores de Acetaldeído Desidrogenases/farmacologia , Carcinoma de Células Escamosas/metabolismo , Cobre/química , Dissulfiram/química , Dissulfiram/farmacologia , Reposicionamento de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Mitocôndrias/efeitos dos fármacos , Neoplasias Bucais/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-myc/metabolismo
11.
Biochem Biophys Res Commun ; 555: 95-101, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33813282

RESUMO

Oral squamous cell carcinoma (OSCC) is a highly aggressive carcinoma with a high incidence of recurrence and distant metastasis. However, the mechanism of epithelial to mesenchymal transition (EMT) during tumor progression and metastasis in OSCC has not yet been fully elucidated. It is well known that the Cl- channel controls cell volume and activates several signaling pathways for cell differentiation. The aim of the present study was to investigate the role of the Cl- channel on EMT in the OSC 20 cell line, which is an OSCC line. OSC-20 cells were cultured with low serum medium containing a Cl- channel blocker NPPB. Morphological changes, gene expression, immunoreactivity, cell volume, and signaling pathway of the NPPB-treated OSC-20 cells were evaluated. The NPPB-treated OSC-20 cells showed typical morphology of mesenchymal cells. The expression levels of the epithelial marker E-cadherin in the NPPB-treated OSC-20 cells were lower than those of the untreated and TGF-ß1-treated OSC-20 cells. On the other hand, mesenchymal markers such as vimentin, ZEB1, and Snail, in the NPPB-treated OSC-20 cells were higher than those in the untreated and TGF-ß1-treated OSC-20 cells. Furthermore, a large number of vimentin-positive cells also appeared in the NPPB-treated OSC-20 cells. Additionally, the cell volume of these cells was significantly increased compared to that of the untreated and TGF-ß1-treated cells. Interestingly, NPPB did not activate the TGF-ß/smad signaling pathway, but activated the Wnt/ß-catenin signaling pathway. These results suggest that Cl- channel dysfunction promoted EMT via activation of the Wnt/ß-catenin signaling pathway in OSCC.


Assuntos
Carcinoma de Células Escamosas/patologia , Canais de Cloreto/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias Bucais/patologia , Antracenos/farmacologia , Antígenos CD/metabolismo , Caderinas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Tamanho Celular/efeitos dos fármacos , Canais de Cloreto/antagonistas & inibidores , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Neoplasias Bucais/metabolismo , Nitrobenzoatos/farmacologia , Tripsina/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
12.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807213

RESUMO

Incidence of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis has increased worldwide, and non-steroidal anti-inflammatory drugs as celecoxib are considered for treatment. We show here strong anti-proliferative effects of celecoxib in four cSCC cell lines, while apoptosis and cell viability largely remained unaffected. Impeded apoptosis was overcome in combinations with agonistic CD95 antibody or TNF-related apoptosis-inducing ligand (TRAIL), resulting in up to 60% apoptosis and almost complete loss of cell viability. Proapoptotic caspase cascades were activated, and apoptosis was suppressed by caspase inhibition. TRAIL receptor (DR5) and proapoptotic Bcl-2 proteins (Puma and Bad) were upregulated, while anti-apoptotic factors (survivin, XIAP, cFLIP, Mcl-1, and Bcl-w) were downregulated. Strongly elevated levels of reactive oxygen species (ROS) turned out as particularly characteristic for celecoxib, appearing already after 2 h. ROS production alone was not sufficient for apoptosis induction but may play a critical role in sensitizing cancer cells for apoptosis and therapy. Thus, the full therapeutic potential of celecoxib may be better used in combinations with death ligands. Furthermore, the immune response against cSCC/AK may be improved by celecoxib, and combinations with checkpoint inhibitors, recently approved for the treatment of cSCC, may be considered.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/metabolismo , Celecoxib/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ligantes , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia
13.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925575

RESUMO

Head and neck squamous cell carcinomas (HNSCCs) are aggressive diseases with a dismal patient prognosis. Despite significant advances in treatment modalities, the five-year survival rate in patients with HNSCC has improved marginally and therefore warrants a comprehensive understanding of the HNSCC biology. Alterations in the cellular and non-cellular components of the HNSCC tumor micro-environment (TME) play a critical role in regulating many hallmarks of cancer development including evasion of apoptosis, activation of invasion, metastasis, angiogenesis, response to therapy, immune escape mechanisms, deregulation of energetics, and therefore the development of an overall aggressive HNSCC phenotype. Cytokines and chemokines are small secretory proteins produced by neoplastic or stromal cells, controlling complex and dynamic cell-cell interactions in the TME to regulate many cancer hallmarks. This review summarizes the current understanding of the complex cytokine/chemokine networks in the HNSCC TME, their role in activating diverse signaling pathways and promoting tumor progression, metastasis, and therapeutic resistance development.


Assuntos
Carcinoma de Células Escamosas/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Microambiente Tumoral/imunologia , Apoptose , Carcinoma de Células Escamosas/metabolismo , Quimiocinas/imunologia , Citocinas/imunologia , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Prognóstico , Transdução de Sinais , Microambiente Tumoral/fisiologia
14.
Mol Med Rep ; 23(6)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33786612

RESUMO

Dioscin, an extract from traditional Chinese herbal plants, displays various biological and pharmacological effects on tumors, including inhibition of cell proliferation and induction of DNA damage. However, the effects of dioscin on oral squamous cell carcinoma (OSCC) cells are not completely understood. The present study aimed to evaluate the impact of dioscin on OSCC cell proliferation. Cell Counting Kit­8 and 5­ethynyl­2'­deoxyuridine incorporation assays were performed to assess cell proliferation. Flow cytometry was conducted to detect alterations in the cell cycle and cell apoptosis. Western blotting and coimmunoprecipitation were performed to determine protein expression levels. In SCC15 cells, dioscin treatment significantly induced cell cycle arrest, increased apoptosis and inhibited proliferation compared with the control group. Mechanistically, the tumor suppressor protein Ras association domain­containing protein 1A (RASSF1A) was activated and oncoprotein yes­associated protein (YAP) was phosphorylated by dioscin. Furthermore, YAP overexpression and knockdown reduced and enhanced the inhibitory effects of dioscin on SCC15 cells, respectively. In summary, the results demonstrated that, compared with the control group, dioscin upregulated RASSF1A expression in OSCC cells, which resulted in YAP phosphorylation, thus weakening its transcriptional coactivation function, enhancing cell cycle arrest and apoptosis, and inhibiting cell proliferation. The present study indicated that dioscin may serve as a therapeutic agent for OSCC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/metabolismo , Proliferação de Células/efeitos dos fármacos , Diosgenina/análogos & derivados , Neoplasias Bucais/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Diosgenina/farmacologia , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética
15.
Front Immunol ; 12: 598671, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717076

RESUMO

Non-small-cell lung cancers (NSCLCs) are largely classified into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), which have different therapeutic options according to its molecular profiles and immune checkpoint expression, especially PD-L1, which is a suppressive factor in the tumor microenvironment. The tumor microenvironment can be altered by the genomic mutations on specific innate immune genes as well as tumor suppressor genes, so it is essential to comprehend the association between tumor microenvironment and tumor suppressor genes to discover the promising immunotherapeutic strategy to overcome the resistance of immune check point blockade. In this study, we aimed to analyze how the somatic mutations in tumor suppressor genes affect the tumor immune microenvironment through a comprehensive analysis of mutational profiling on the representative tumor suppressor genes (TP53, CDKN2A, PTEN, RB1, BRCA1, BRCA2) and immune gene expression in The Cancer Genome Atlas (TCGA) 155 lung squamous cell carcinoma (LUSC) and 196 lung adenocarcinoma (LUAD) samples. Several microenvironmental factors, such as the infiltrating immune and stromal cells, were suppressed by the mutated tumor suppressor genes in LUSC, unlike in the LUAD samples. In particular, infiltrating immune cells such as macrophage, neutrophil, and dendritic cells were significantly reduced in tumors with mutated tumor suppressor genes' group. In addition, the gene expressions for interleukin production and lymphocyte differentiation and PGC, C7, HGF, PLA2G2A, IL1RL1, CCR2, ALOX15B, CXCL11, FCN3 were significantly down-regulated, which were key immune genes for the cross-talk between LUSC microenvironment and tumor suppressors. Therefore, we generated evidence that TSG mutations in LUSC have an impact on tumor immune microenvironment, which suggests that TSG non-mutated patients will have the more inflamed tumors and are more likely to respond to immune checkpoint blockade therapy.


Assuntos
Carcinoma de Células Escamosas/etiologia , Perfilação da Expressão Gênica , Genes Supressores de Tumor , Genômica , Neoplasias Pulmonares/etiologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Biomarcadores Tumorais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Mutação , Modelos de Riscos Proporcionais , Transcriptoma
16.
Aging (Albany NY) ; 13(5): 7284-7299, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33653965

RESUMO

Glycolysis markers including glucose transporter 1 (GLUT1), monocarboxylate transporter 4 (MCT4), hexokinase 2 (HK2), pyruvate kinase M2 (PKM2) and glucose transporter 4 (GLUT4) play vital roles in head and neck squamous cell carcinoma (HNSCC). However, their prognostic value in HNSCC is still controversial. In this meta-analysis, we searched the PubMed, Web of Science and Cochrane Library databases and included thirty-seven studies (3272 patients) that met the inclusion criteria. Higher expression levels of the glycolysis markers in tumor tissues correlated with poorer overall survival (OS; P < 0.001), disease-free survival (DFS; P = 0.03) and recurrence-free survival (RFS; P < 0.001) of HNSCC patients. Subgroup and sensitivity analyses demonstrated that higher expression levels of GLUT1 (P < 0.001), MCT4 (P = 0.002), HK2 (P = 0.002) and PKM2 (P < 0.001) correlated with poorer OS among HNSCC patients. Higher expression of MCT4 (P < 0.001) and PKM2 (P = 0.008) predicted poorer DFS among HNSCC patients. However, GLUT4 expression levels did not associate with clinical outcomes in HNSCC patients. These results demonstrate that glycolysis markers, such as GLUT1, MCT4, HK2 and PKM2, are potential prognostic predictors and therapeutic targets in HNSCC.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Glicólise , Neoplasias de Cabeça e Pescoço/diagnóstico , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Proteínas de Transporte/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Hexoquinase/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Prognóstico , Hormônios Tireóideos/metabolismo
17.
Aging (Albany NY) ; 13(5): 7259-7283, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33658400

RESUMO

The fuzzy planar cell polarity protein (Fuz) is an effector component of the planar cell polarity (PCP) signaling. Together with other core and effector proteins, the PCP pathway controls polarized cell movements. Fuz was also reported as a negative regulator of cell survival. In this study, we performed a pan-cancer survey to demonstrate the role of Fuz in multiple types of cancer. In head-neck squamous cell carcinoma and lung adenocarcinoma tumor samples, a reduction of Fuz transcript expression was detected. This coincides with the poor overall survival probabilities of these patients. We further showed that Fuz promoter hypermethylation contributes to its transcriptional downregulation. Meanwhile, we also identified a relatively higher mutation frequency at the 404th arginine amino acid residue in the coding sequence of Fuz locus, and further demonstrated that mutant Fuz proteins perturb the pro-apoptotic function of Fuz. In summary, our study unveiled an intriguing relationship between Fuz dysregulation and cancer prognosis, and further provides mechanistic insights of Fuz's involvement in carcinogenesis.


Assuntos
Carcinogênese/metabolismo , Proteínas do Citoesqueleto/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/etiologia , Adenocarcinoma de Pulmão/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/metabolismo , Polaridade Celular , Metilação de DNA , Feminino , Genes Neoplásicos , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Masculino , Prognóstico
18.
Oncology ; 99(6): 402-412, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33756477

RESUMO

BACKGROUND: Cancer stem cells (CSC) are cells that exhibit stem cell properties and are pivotal in tumor biology. CSC markers have been described for many tumorous entities. However, to this date, there is no data on CSC markers in respect to squamous cell carcinomas (SCC) of the salivary glands. METHODS: Histologic samples from patients with salivary gland SCCs were stained for CSC markers (ALDH-1/BMI-1/SOX-2/CD-44/vimentin) and divided into high and low expression subgroups. These were then correlated with tumor and patient characteristics as well as overall survival (OS), disease-specific survival, recurrence-free survival and local control rates (LCR) after 3 and 5 years. RESULTS: Overall, 31 samples were included. CD-44 and ALDH-1 expression were associated with tumor origin (metastatic/primary disease, p = 0.048 and p = 0.011, respectively). Strong BMI-1 expression was associated with poorer OS (62.9 vs. 27.3%, p = 0.029), strong SOX-2 expression was associated with poorer LCR (62.5 vs. 21.9%, p = 0.007). CONCLUSION: CD-44 and ALDH-1 may be useful in differentiating between primary SCCs and metastatic disease. BMI-1 and SOX-2 are correlated with poorer prognosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Células-Tronco Neoplásicas/metabolismo , Neoplasias das Glândulas Salivares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Família Aldeído Desidrogenase 1/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Diagnóstico Diferencial , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Complexo Repressor Polycomb 1/metabolismo , Prognóstico , Retinal Desidrogenase/metabolismo , Estudos Retrospectivos , Fatores de Transcrição SOXB1/metabolismo , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/secundário , Análise de Sobrevida
19.
FASEB J ; 35(4): e21539, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33742719

RESUMO

An aberrant accumulation of nuclear ß-catenin is closely associated with the augmentation of cancer malignancy. In this work, we report that several microtubule-targeting agents (MTAs) such as vinblastine, taxol, and C12 (combretastatin-2-aminoimidazole analog) inhibit Wnt/ß-catenin signaling in oral squamous cell carcinoma (OSCC). We showed that the inhibition of microtubule dynamics by MTAs decreased the level of ß-catenin by increasing Axin and adenomatous polyposis coli levels and reducing the level of dishevelled. Furthermore, MTAs strongly reduced the localization of ß-catenin in the nucleus. The reduction in the level of nuclear ß-catenin was neither due to the degradation of ß-catenin in the nucleus nor due to an increase in the export of nuclear ß-catenin from the nucleus. A motor protein kinesin-2 was found to assist the nuclear transportation of ß-catenin. Interestingly, Wnt/ß-catenin signaling antagonist treatment synergized with MTAs and the activators of Wnt/ß-catenin signaling antagonized with the MTAs. C12 potently suppressed the growth of 4-Nitroquinoline 1-oxide-induced OSCC in the tongue of C57 black 6 mice and also abrogated Wnt/ß-catenin signaling pathway in the tumor. Our results provide evidence that the decrease in Wnt/ß-catenin signaling is an important antitumor effect of MTAs and the combined use of MTAs with Wnt/ß-catenin signaling antagonists could be a promising strategy for cancer chemotherapy.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Microtúbulos/metabolismo , Neoplasias Bucais/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , beta Catenina/metabolismo , Transporte Ativo do Núcleo Celular/fisiologia , Animais , Linhagem Celular Tumoral , Humanos , Camundongos Endogâmicos C57BL , Via de Sinalização Wnt/fisiologia
20.
J Biochem Mol Toxicol ; 35(6): 1-8, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33704875

RESUMO

In recent years, many researchers have made tremendous efforts into using nanotechnology in biomedical applications and science, such as magnetic resonance imaging, drug delivery, and in particular, oncological therapeutic via superparamagnetic iron oxide nanoparticles (SPIONs). Head and neck squamous cell carcinoma (HNSCC) and especially oral squamous cell carcinoma (OSCC) have been a serious and ongoing concern. There are many strong emphases on the importance of toxic mechanisms due to oxidative stress and specifically, the changed cellular response. Therefore, our study was designed to evaluate the effects of SPIONs on OSCC mitochondria because of the usefulness of the application of these nanoparticles in cancer treatment and diagnosis. An increased level of reactive oxygen species (ROS) is one of the substantial mechanisms found for SPIONs in this study, and initially originated from disruption of the electron transfer chain shown by a decrease in mitochondrial succinate dehydrogenase activity. Increased ROS formation subsequently followed a decline of mitochondrial membrane potential, the release of mitochondrial cytochrome complex, and mitochondrial swelling in the OSCC mitochondria compared with almost no effect in normal mitochondria. In addition, the SPIONs decreased cell viability and increased lipid peroxidation level and caspase-3 activity in OSCC cells. The results represented that the exposure to the SPIONs induced selective toxicity only on the OSCC but not normal mitochondria. Based on our findings, we finally concluded that the SPIONs may be considered as a potential therapeutic candidate for the treatment of OSCC.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Citotoxinas/farmacologia , Sistemas de Liberação de Medicamentos , Nanopartículas Magnéticas de Óxido de Ferro/química , Mitocôndrias/metabolismo , Neoplasias Bucais/tratamento farmacológico , Animais , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Citotoxinas/química , Mitocôndrias/patologia , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/metabolismo , Ratos
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