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1.
Adv Exp Med Biol ; 1268: 171-191, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32918219

RESUMO

The prevalent keratinocyte-derived neoplasms of the skin are basal cell carcinoma and squamous cell carcinoma. Both so-called non-melanoma skin cancers comprise the most common cancers in humans by far. Common risk factors for both tumor entities include sun exposure, DNA repair deficiencies leading to chromosomal instability, or immunosuppression. Yet, fundamental differences in the development of the two different entities have been and are currently unveiled. The constitutive activation of the sonic hedgehog signaling pathway by acquired mutations in the PTCH and SMO genes appears to represent the early basal cell carcinoma developmental determinant. Although other signaling pathways are also affected, small hedgehog inhibitory molecules evolve as the most promising basal cell carcinoma treatment options systemically as well as topically in current clinical trials. For squamous cell carcinoma development, mutations in the p53 gene, especially UV-induced mutations, have been identified as early events. Yet, other signaling pathways including epidermal growth factor receptor, RAS, Fyn, or p16INK4a signaling may play significant roles in squamous cell carcinoma development. The improved understanding of the molecular events leading to different tumor entities by de-differentiation of the same cell type has begun to pave the way for modulating new molecular targets therapeutically with small molecules.


Assuntos
Carcinoma Basocelular , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Carcinoma Basocelular/metabolismo , Carcinoma de Células Escamosas/metabolismo , Proteínas Hedgehog/metabolismo , Humanos , Terapia de Alvo Molecular , Transdução de Sinais , Neoplasias Cutâneas/metabolismo
2.
PLoS One ; 15(8): e0237465, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785290

RESUMO

BACKGROUND: Tumor-infiltrating lymphocytes include tumor-reactive lymphocytes and regulatory T-cells. However, the prognostic value of tumor-infiltrating lymphocytes in oral squamous cell carcinoma (OSCC) remains unclear. METHODS: We used immunohistochemistry to evaluate the presence of tumor-infiltrating FoxP3⁺ T-cells and CTLA-4⁺ cells in four distinct histological compartments (tumor parenchyma and stroma at the tumor center, and parenchyma and stroma at the invasive front) and assessed the association between the prevalence of these cells and the histopathological status of 137 patients with OSCC. RESULTS: Five-year overall survival, disease-specific survival, and recurrence-free survival were favorable in patients with high numbers of FoxP3⁺ T-cells in the parenchyma of the invasive front. Recurrence-free survival and metastasis-free survival were decreased in patients with high numbers of CTLA-4⁺ cells in the parenchyma of the invasive front. CONCLUSIONS: The presence of FoxP3⁺ T-cells in the parenchyma of the invasive front may be a useful prognostic factor. Our results indicate that FoxP3⁺ T-cells may exert site-specific anti-tumor effects but may not play an immunosuppressive role in OSCC. In addition, our results suggest that CTLA-4+ cells suppress the function of FoxP3+ T-cells and promote anti-tumor immunity in OSCC.


Assuntos
Antígeno CTLA-4/metabolismo , Carcinoma de Células Escamosas/patologia , Fatores de Transcrição Forkhead/metabolismo , Neoplasias Bucais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Feminino , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Neoplasias Bucais/mortalidade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo
3.
J Cancer Res Ther ; 16(3): 401-404, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719243

RESUMO

To review the relevance of sialic acid as a tumour marker in oral cancer. Tumour marker are useful in the screening for early malignancy. Sialic acids are important in determining the surface properties of cells and has been implicated in cellular invasiveness, adhesiveness, and immunogenicity. Sialic acids are commonly found at the outermost end of glycan chains of all cell types. Increase in the levels of sialic acid in oral cancer indicates its importance as a tumour marker.Both serum and salivary sialic acid levels can be used as a screening tool and a diagnostic aid for oral cancer. Salivary sialic acid can be used as a non-invasive, cost effective and reliable diagnostic methods for screening and monitoring of oral cancer. In patients with oral cancer, glycoprotein metabolism is altered. Increase in the levels of sialic acid in oral cancer indicate its importance as a tumour marker. Changes in the serum is reflected in saliva. Salivary sialic acid can be used as non-invasive, cost effective and reliable diagnostic methods for screening and monitoring of oral cancer. Early the diagnosis, better the prognosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Bucais/diagnóstico , Ácido N-Acetilneuramínico/análise , Lesões Pré-Cancerosas/diagnóstico , Saliva/metabolismo , Carcinoma de Células Escamosas/metabolismo , Humanos , Neoplasias Bucais/metabolismo , Lesões Pré-Cancerosas/metabolismo , Prognóstico , Saliva/química
4.
J Cancer Res Ther ; 16(3): 452-457, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719250

RESUMO

Introduction: Cytokeratin fragment 21-1 (CYFRA21-1), a constituent of the intermediate filament protein is known to be elevated in cancer. In vitro cleavage of cytokeratin 19 (CK19) protein results in the release of it's fragments into the supernatants of premalignant cell lines. This study was designed with the aim to investigate the concentrations of CYFRA21-1 in serum and saliva of oral potentially malignant disorders (OPMD), to evaluate CK19 expression in tissues of the same patients and to correlate the levels of CYFRA21-1 concentration in serum and saliva with CK19 expression in OPMDs, and to compare it with oral squamous cell carcinoma (OSCC), which was taken as positive control. Materials and Methods: Concentration of CYFRA21-1 was measured in saliva and serum of 30 OPMD cases with five patients having OSCC using ELISA technique and analysis of CK19 protein expression in the tissue of same patients using immunohistochemical technique was done. Results: Concentration of CYFRA21-1 in saliva and serum with regard to CK19 protein expression in tissues was significantly higher in control group than in study groups. Conclusion: CYFRA21-1 can be used as a promising diagnostic molecule and as an adjunctive marker for early detection, disease staging, and monitoring.


Assuntos
Antígenos de Neoplasias/análise , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Queratina-19/análise , Queratina-19/metabolismo , Neoplasias Bucais/diagnóstico , Lesões Pré-Cancerosas/diagnóstico , Saliva/metabolismo , Adulto , Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Lesões Pré-Cancerosas/metabolismo
5.
J Cancer Res Ther ; 16(3): 494-499, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719256

RESUMO

Introduction: Conventional oral squamous cell carcinoma (OSCC) is relatively easy to diagnose on histopathology, as it comprises dysplastic epithelial cells with variable degrees of squamous differentiation. Different grading systems have been employed in grading OSCC based on its dysplastic features and host response. Some unusual features such as clear cell change, epithelial-mesenchymal transition (EMT), stromal hyalinization, stromal desmoplasia, perineural invasion, vascular invasion, tissue eosinophilia, giant cells, and tertiary lymphoid follicle formation are evident in OSCC histologically but have not yet been accounted in any grading systems of OSCC except perineural and vascular invasion. Aim: The aim of the present study was to identify these uncommon features and to correlate them with different grades of OSCC.Materials and Methods:This study was conducted on 100 histopathologically confirmed OSCC cases retrieved from the archives of our department. They were graded on the basis of Broder's grading system and were reviewed for the features mentioned above. Data collected were subjected to statistical analysis. Results: Clear cell change, EMT, foreign body giant cells, and tumor giant cells were observed in 13%, 20%, 1%, and 3% of cases, respectively. We found stromal desmoplasia in 15% and stromal hyalinization in 9% of cases. Tissue eosinophilia, tertiary lymphoid follicle formation, and perineural invasion were observed in 12%, 3%, and 2% of cases, respectively. Vascular invasion was not evident in any of the cases examined. Conclusion: The incidence of the unusual features was 7.8% in our study.


Assuntos
Carcinoma de Células Escamosas/patologia , Eosinófilos/patologia , Transição Epitelial-Mesenquimal , Neoplasias Bucais/patologia , Adulto , Idoso , Carcinoma de Células Escamosas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
6.
Gene ; 757: 144936, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32640301

RESUMO

Oral squamous cell carcinoma (OSCC) accounts for nearly 90 percent of oral cavity malignancies and is one of the most widespread oral cancers in the world. The microRNAs (miRNAs or miRs) have an important role in cellular processes comprising cell cycle, differentiation, and also apoptosis. MiRNAs are also implicated in the progression of cancers, including OSCC, through a variety of signaling pathways. One of the most significant signaling pathways in OSCC is the PI3K / Akt pathway that has been illustrated to be under the tight regulation of miRNAs. Deregulation or activation of the PI3K / Akt pathway due to mutations has been revealed to be implicated in the development of oral cancer. According to studies, more than 47% of HNSCC and around 38% of OSCC samples indicate at least one molecular alteration in this signaling pathway. The potential of miRNAs for their use as therapeutic tools in the diagnosis as well as treatment of numerous diseases have been confirmed. In the current review, we summarize miRNAs and their possible mechanisms as well as their functions in OSCC advancement and progression.


Assuntos
Carcinoma de Células Escamosas/genética , MicroRNAs/genética , Neoplasias Bucais/genética , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo
7.
Anticancer Res ; 40(7): 3685-3696, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620607

RESUMO

BACKGROUND/AIM: Although chemotherapy agents, such as oxaliplatin, cisplatin, paclitaxel and bortezomib frequently cause severe peripheral neuropathy, very few studies have reported the effective strategy to prevent this side effect. In this study, we first investigated whether these drugs show higher neuropathy compared to a set of 15 other anticancer drugs, and then whether antioxidants, such as sodium ascorbate, N-acetyl-L-cysteine, and vitamin B12 have any protective effect against them. MATERIALS AND METHODS: Rat PC12 cells were induced to differentiate into neuronal cells by repeated overlay of serum-free medium supplemented with nerve growth factor. The cytotoxic levels of anticancer drugs against four human oral squamous cell carcinoma cell lines, three normal oral cells, and undifferentiated and differentiated PC12 cells were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Cells were sorted for apoptotic cells (distributed into subG1 phase) and cells at different stages of cell cycle (G1, S and G2/M). RESULTS: All 19 anticancer drugs showed higher cytotoxicity against PC12 compared to oral normal cells. Among them, bortezomib showed the highest cytotoxicity against both undifferentiated and differentiated PC12 cell and, committed them to undergo apoptosis. Sodium ascorbate and N-acetyl-L-cysteine, but not vitamin B12, completely reversed the cytotoxicity of bortezomib. CONCLUSION: Bortezomib-induced neuropathy might be ameliorated by antioxidants.


Assuntos
Antioxidantes/farmacologia , Bortezomib/efeitos adversos , Síndromes Neurotóxicas/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Bortezomib/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Fator de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Síndromes Neurotóxicas/metabolismo , Células PC12 , Doenças do Sistema Nervoso Periférico/metabolismo , Ratos
8.
Science ; 369(6501)2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32675345

RESUMO

Targeting the cross-talk between tumor-initiating cells (TICs) and the niche microenvironment is an attractive avenue for cancer therapy. We show here, using a mouse model of squamous cell carcinoma, that TICs play a crucial role in creating a niche microenvironment that is required for tumor progression and drug resistance. Antioxidant activity in TICs, mediated by the transcription factor NRF2, facilitates the release of a nuclear cytokine, interleukin-33 (IL-33). This cytokine promotes differentiation of macrophages that express the high-affinity immunoglobulin E receptor FcεRIα and are in close proximity to TICs. In turn, these IL-33-responding FcεRIα+ macrophages send paracrine transforming growth factor ß (TGF-ß) signals to TICs, inducing invasive and drug-resistant properties and further upregulating IL-33 expression. This TIC-driven, IL-33-TGF-ß feedforward loop could potentially be exploited for cancer treatment.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Interleucina-33/metabolismo , Células-Tronco Neoplásicas/patologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Progressão da Doença , Humanos , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais , Microambiente Tumoral
9.
PLoS One ; 15(7): e0236101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32678829

RESUMO

Dysregulation of histone demethylase Jumonji-C domain-containing protein 5 (JMJD5) has been identified as a great effect on tumorigenesis. Silibinin is a commonly used anti-hepatotoxic drug and exhibits anticancer effect in various cancers. However, the antitumor mechanism between silibinin and JMJD5 in oral squamous cell carcinoma (OSCC) remains unclear. In this study, the clinical significance of JMJD5 on OSCC patients was assessed through tissue microarray. Furthermore, mice bearing patient-derived tumor xenografts (PDTXs) and tongue cancer cell lines were treated with silibinin and evaluated for tumor growth and JMJD5 expression. High expression of JMJD5 in oral cancer was significantly associated with tumor size (P = 0.0241), cervical node metastasis (P = 0.0001) and clinical stage (P = 0.0002), was associated with worse survival rate compared with that of the total cohort (P = 0.0002). Collectively the data indicate that JMJD5 expression may be suitable for detection of unfavorable prognosis in OSCC patients, based in part on its apparent role as a marker of metastasis. In addition, silibinin inhibits cancer growth in vitro and in PDTX models. Furthermore, metastasis-associated protein 1 (MTA1) could regulate the expression for JMJD5 and had a positive correlation with JMJD5. Moreover, silibinin could downregulate JMJD5 and MTA1 in oral cancer. Present study thus identifies that JMJD5 might be an essential prognostic indicator and therapeutic target against OSCC progression. In addition, silibinin is a potential candidate among novel chemotherapeutic agents or adjuvants for modulating JMJD5 in OSCC, through a mechanism likely involving MTA1/JMJD5 axis.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Histona Desmetilases/metabolismo , Neoplasias Bucais/patologia , Proteínas Repressoras/metabolismo , Silibina/farmacologia , Transativadores/metabolismo , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/genética , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Prognóstico , Proteínas Repressoras/genética , Taxa de Sobrevida , Transativadores/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Life Sci ; 257: 118104, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679143

RESUMO

Halofuginone (HF) from Dichroa febrifuga has shown therapeutic potential in hepatocellular, lung and colorectal cancer cell models. Evidence has also indicated that HF plays roles in caustic induced esophageal strictures and oxidative injury. However, the role of HF in esophageal squamous carcinoma (ESCC) remains unclear. In this study, we investigated HF actions and mechanisms during ESCC cell apoptosis. We observed different HF concentrations (5, 10 and 20 nM) inhibited ESCC cell survival in a time and dose-dependent manner. HF treatment markedly induced KYSE-30 and TE-1 cell apoptosis, and caspase-3 activity. Apoptosis related protein Bax expression was dramatically increased, whereas Bcl-2 levels were reduced in KYSE-30 and TE-1 cells, after HF exposure. Also, we showed that HF treatment induced DNA damage by promoting γH2AX, pATM and pATR expression. HF treatment also reduced hypoxia-inducible factor-1α (HIF-1α) and forkhead box class O 3a (FOXO3a) expression in KYSE-30 and TE-1 cells. We also showed that HF inhibited FOXO3a expression, but this was dependent on HIF-1α inhibition. Finally, FOXO3a overexpression reversed HF induced cell survival inhibition, cell apoptosis and DNA damage. FOXO3a knockdown enhanced the effects of HF on cell survival, cell apoptosis and DNA damage. In summary, HF plays inhibitory roles in ESCC cell apoptosis, via HIF-1α-FOXO3a-dependent signaling. These data support the notion that HF could act as an effective therapeutic reagent towards ESCC.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Esofágicas/tratamento farmacológico , Proteína Forkhead Box O3/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Piperidinas/uso terapêutico , Quinazolinonas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Western Blotting , Carcinoma de Células Escamosas/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Neoplasias Esofágicas/metabolismo , Humanos
11.
Proc Natl Acad Sci U S A ; 117(28): 16167-16173, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601197

RESUMO

Saliva is a noninvasive biofluid that can contain metabolite signatures of oral squamous cell carcinoma (OSCC). Conductive polymer spray ionization mass spectrometry (CPSI-MS) is employed to record a wide range of metabolite species within a few seconds, making this technique appealing as a point-of-care method for the early detection of OSCC. Saliva samples from 373 volunteers, 124 who are healthy, 124 who have premalignant lesions, and 125 who are OSCC patients, were collected for discovering and validating dysregulated metabolites and determining altered metabolic pathways. Metabolite markers were reconfirmed at the primary tissue level by desorption electrospray ionization MS imaging (DESI-MSI), demonstrating the reliability of diagnoses based on saliva metabolomics. With the aid of machine learning (ML), OSCC and premalignant lesions can be distinguished from the normal physical condition in real time with an accuracy of 86.7%, on a person by person basis. These results suggest that the combination of CPSI-MS and ML is a feasible tool for accurate, automated diagnosis of OSCC in clinical practice.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Metabolômica , Neoplasias Bucais/diagnóstico , Saliva/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Estadiamento de Neoplasias , Testes Imediatos , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray
12.
Immunol Med ; 43(3): 121-129, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32546118

RESUMO

The roles of interleukin-22 (IL-22) in carcinogenesis have been proposed in various neoplasms. Increased expression of IL-22 has been observed in oral squamous cell carcinoma (OSCC) lesions as well as in other cancers. OSCC is still associated with poor prognosis and a high mortality rate because of its invasiveness and frequent lymph node metastasis. In the present study, we investigated the effects of IL-22 on OSCC cells. The human OSCC cell lines Ca9-22 and SAS were stimulated with IL-22 (1-10 ng/mL), and their migration abilities were examined using a cell scratch assay. A Matrigel invasion assay was performed to evaluate the invasion abilities of OSCC cells. Signal transducer and activator of transcription 3 (STAT3) phosphorylation, matrix metalloproteinase (MMP) and epithelial-mesenchymal transition (EMT)-related genes and proteins were also examined. IL-22 treatment promoted the migration and invasion abilities of OSCC cells without increasing their viability. IL-22 stimulation also induced STAT3 phosphorylation, MMP-9 activity and EMT-related genes and proteins. Our findings suggest that IL-22 has possible roles in the development of OSCC.


Assuntos
Carcinoma de Células Escamosas/patologia , Movimento Celular/efeitos dos fármacos , Interleucinas/efeitos adversos , Interleucinas/fisiologia , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Humanos , Metástase Linfática/genética , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Invasividade Neoplásica/genética , Fosforilação/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
13.
Anticancer Res ; 40(5): 2467-2474, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366390

RESUMO

BACKGROUND/AIM: The hormonally-active form of vitamin D, 1,25(OH)2D3, demonstrated activity against oral squamous cell carcinoma (OSCC). Cytochrome P450scc (CYP11A1)-derived vitamin D hydroxyderivatives, such as 20(OH)D3 and 1,20(OH)2D3, have overlapping beneficial effects with 1,25(OH)2D3 without causing hypercalcemia. This study sought to determine (i) whether 20(OH)D3 and 1,20(OH)2D3 exhibit antitumor effects against OSCC comparable to those of 1,25(OH)2D3 and (ii) whether these effects may stem from down-regulation of sonic hedgehog (SHH) or WNT/ß-catenin signaling pathways. MATERIALS AND METHODS: Effects on CAL-27 cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt and spheroid assays. Signaling pathways were assessed by immunofluorescence and western blotting. RESULTS: 20(OH)D3 and 1,20(OH)2D3 inhibited the growth of CAL-27 and demonstrated inhibition of WNT/ß-catenin and the SHH signaling as evidenced by down-regulation of nuclear translocation of glioma-associated oncogene 1(GLI1) and ß-catenin. CONCLUSION: Noncalcemic vitamin D hydroxyderivatives demonstrated antitumor activities against OSCC comparable to those of 1,25(OH)2D3 Their activities against SHH and the WNT/ß-catenin pathways provide insight for a possible target for OSCC treatment.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/metabolismo , Proteínas Hedgehog/metabolismo , Neoplasias Bucais/metabolismo , Vitamina D/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Biomarcadores , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Núcleo Celular , Imunofluorescência , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/etiologia , Neoplasias Bucais/patologia , Transporte Proteico , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico , beta Catenina/metabolismo
14.
Life Sci ; 254: 117695, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32407849

RESUMO

AIMS: To investigate the therapeutic potential of itraconazole in oral squamous cell carcinoma (OSCC) and its molecular mechanism. MATERIALS AND METHODS: The in vitro anti-cancer effects of itraconazole was determined by CCK-8 assay and colony formation assay. Transwell and wound healing assays were used to examine cell invasion and migration. The in vivo therapeutic efficacy of itraconazole was assessed by OSCC patient-derived xenograft (PDX) model. Western blot was performed to explore the anti-cancer mechanism. KEY FINDINGS: Itraconazole inhibited cell proliferation and colony formation of OSCC cells in a time and concentration dependent manner; induced cell cycle arrest and apoptosis, as well as inhibited cell invasion and migration. In the OSCC PDX model, itraconazole impeded tumor growth, reduced Ki-67 expression and induced apoptosis. Itraconazole downregulated the protein expression of Hedgehog pathway to inhibit proliferation and migration of oral squamous cell carcinoma cells, which can be revised by recombinant human sonic hedgehog protein (rSHH). SIGNIFICANCE: Itraconazole showed anti-cancer effects on OSCC via inhibiting the Hedgehog pathway.


Assuntos
Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/patologia , Proteínas Hedgehog/antagonistas & inibidores , Itraconazol/farmacologia , Neoplasias Bucais/patologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Bucais/metabolismo
15.
Nat Commun ; 11(1): 2124, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358507

RESUMO

Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.


Assuntos
Carcinoma de Células Escamosas/terapia , Imunoterapia/métodos , Neoplasias Penianas/terapia , Animais , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular , Cisplatino/farmacologia , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/metabolismo , Neoplasias Penianas/metabolismo , Proteômica , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Análise Serial de Tecidos , Transcriptoma/genética
16.
Cancer Sci ; 111(7): 2385-2399, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32385953

RESUMO

The tumor microenvironment (TME) consists of various components including cancer cells, tumor vessels, cancer-associated fibroblasts (CAFs), and inflammatory cells. These components interact with each other via various cytokines, which often induce tumor progression. Thus, a greater understanding of TME networks is crucial for the development of novel cancer therapies. Many cancer types express high levels of TGF-ß, which induces endothelial-to-mesenchymal transition (EndMT), leading to formation of CAFs. Although we previously reported that CAFs derived from EndMT promoted tumor formation, the molecular mechanisms underlying these interactions remain to be elucidated. Furthermore, tumor-infiltrating inflammatory cells secrete various cytokines, including TNF-α. However, the role of TNF-α in TGF-ß-induced EndMT has not been fully elucidated. Therefore, this study examined the effect of TNF-α on TGF-ß-induced EndMT in human endothelial cells (ECs). Various types of human ECs underwent EndMT in response to TGF-ß and TNF-α, which was accompanied by increased and decreased expression of mesenchymal cell and EC markers, respectively. In addition, treatment of ECs with TGF-ß and TNF-α exhibited sustained activation of Smad2/3 signals, which was presumably induced by elevated expression of TGF-ß type I receptor, TGF-ß2, activin A, and integrin αv, suggesting that TNF-α enhanced TGF-ß-induced EndMT by augmenting TGF-ß family signals. Furthermore, oral squamous cell carcinoma-derived cells underwent epithelial-to-mesenchymal transition (EMT) in response to humoral factors produced by TGF-ß and TNF-α-cultured ECs. This EndMT-driven EMT was blocked by inhibiting the action of TGF-ßs. Collectively, our findings suggest that TNF-α enhances TGF-ß-dependent EndMT, which contributes to tumor progression.


Assuntos
Transição Epitelial-Mesenquimal , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Biomarcadores , Fibroblastos Associados a Câncer/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular , Células Cultivadas , Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , NF-kappa B/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Microambiente Tumoral/genética , Fator de Necrose Tumoral alfa/farmacologia
17.
Invest Ophthalmol Vis Sci ; 61(5): 15, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32396634

RESUMO

Purpose: Previously, we demonstrated that Krüppel-like factor 4 (KLF4) promotes corneal epithelial (CE) homeostasis by suppressing epithelial-mesenchymal transition (EMT) and TGF-ß signaling. As TGF-ß affects epithelial apicobasal polarity (ABP) and plane of division, we investigated the role of KLF4 in these processes. Methods: Klf4 was ablated in adult ternary transgenic Klf4Δ/ΔCE (Klf4LoxP/LoxP/Krt12rtTA/rtTA/Tet-O-Cre) mouse CE using doxycycline chow. ABP and plane of division markers' expression in Klf4Δ/ΔCE and human ocular surface squamous neoplasia (OSSN) tissues relative to controls was evaluated by quantitative PCR, immunoblots, and/or immunofluorescent staining. Results: Klf4Δ/ΔCE CE cells displayed downregulation of apical Pals1 and Crumbs1, apicolateral Par3, and basolateral Scribble, as well as upregulation of Rho family GTPase Cdc42, suggesting disruption of ABP. Phalloidin staining revealed that the Klf4Δ/ΔCE CE actin cytoskeleton is disrupted. Klf4Δ/ΔCE cells favored vertical plane of division within 67.5° to 90° of the CE basement membrane (39% and 47% of the dividing cells relative to 23% and 26% in the control based on phospho-histone-H3 and survivin, respectively), resulting in more dividing cells within the Klf4Δ/ΔCE CE as reported previously. KLF4 was downregulated in human OSSN tissues that displayed EMT and downregulation of PAR3, PALS1, and SCRIB, consistent with a protective role for KLF4. Conclusions: By demonstrating that Klf4 ablation affects CE expression of ABP markers and Cdc42, cytoskeletal actin organization, and the plane of cell division and that KLF4 is downregulated in OSSN tissues that display EMT and lack ABP, these results elucidate the key integrative role of KLF4 in coordinating CE cell polarity and plane of division, loss of which results in OSSN.


Assuntos
Divisão Celular , Polaridade Celular , Epitélio Anterior/citologia , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proteínas de Ciclo Celular/metabolismo , Neoplasias da Túnica Conjuntiva/metabolismo , Neoplasias da Túnica Conjuntiva/patologia , Regulação para Baixo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Núcleosídeo-Fosfato Quinase/metabolismo , Regulação para Cima , Proteína cdc42 de Ligação ao GTP/metabolismo
18.
Cutis ; 105(3): 138-142;E5, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32352432

RESUMO

Nonmelanoma skin cancer (NMSC) is the most common malignancy worldwide, and the incidence continues to increase. Originally, treatment options for NMSCs largely relied on destructive and surgical methods. Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) commonly are treated with cryosurgery, electrodesiccation and curettage, or more definitive surgical options. Over time, topical agents such as 5-fluorouracil, imiquimod, ingenol mebutate, and various forms of aminolevulinic acid (ALA) for photodynamic therapy (PDT) were included for superficial lesions as well as field treatment. The development of oral hedgehog (Hh) inhibitors such as vismodegib offered a promising alternative to patients with advanced disease. Each treatment has its own specific indications and side effects, thus there is always room for novel therapeutic approaches. We review new and potential treatments for NMSCs since 2018 including topical sonidegib, cemiplimab, taladegib, posaconazole, radiation therapy (RT), combination RT with vismodegib, PDT, and laser therapies.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Basocelular/terapia , Carcinoma de Células Escamosas/terapia , Neoplasias Cutâneas/terapia , Carcinoma Basocelular/metabolismo , Carcinoma de Células Escamosas/metabolismo , Humanos , Terapia a Laser , Fotoquimioterapia , Radioterapia , Neoplasias Cutâneas/metabolismo
19.
Gene ; 749: 144669, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32298761

RESUMO

Lung squamous cell carcinoma (LUSC) is a common type of malignancy. The mechanism behind its tumor progression is not clear yet. The aim of this study is to use machine learning to identify the feature miRNAs, which can be reliably used as biomarkers for diagnosis LUSC. We downloaded microRNA expression data and clinical data from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus(GEO) database to identify differences in microRNA expression of primary tumor tissues and para-carcinoma tissues from LUSC. Construction of miRNA-mRNA interaction network, GO, KEGG pathway analysis and Kaplan-Meier survival analysis were used to explore the biological functions of the identified microRNAs. 21 feature miRNAs were identified between lung SCC tumor tissues and para-carcinoma tissues with the support of SVM and PCA methods. Among them, ten feature miRNAs: mir-143, mir-100, mir-101-1, mir-101-2, mir-182, mir-183, mir-205, mir-21, mir-30a, mir30-d were identified which could be used as a feature group to separate the cancer tissues from the adjacent tissues ultimately, and cross-validation of the obtained data showed that it can achieve extremely high accuracy and recall rate. Using KEGG, Reactome, GO databases, these 10 miRNAs and their target genes were found to be highly correlated with cancer. Survival analysis found that this group of miRNAs had a significant relationship with the survival rate of cancer patients, and the expression was significantly different between tumor tissues and healthy tissues. The dysregulated feature miRNAs might be involved in the pathology of LUSC and could be used as potential diagnostic biomarkers or therapeutic targets for LUSC.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Aprendizado de Máquina , MicroRNAs/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo
20.
J Cancer Res Clin Oncol ; 146(7): 1647-1658, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32335720

RESUMO

BACKGROUND: Additional prognostic factors and personalized therapeutic alternatives for vulvar squamous cell carcinoma (VSCC), especially for advanced stages with poor prognosis, are urgently needed. OBJECTIVES: To review and assess literature regarding underlying molecular mechanisms of VSCC target therapeutic and prognostic approaches. METHODS: We performed a narrative literature review from the inception of the database up to January 2020 limited to English language, organizing knowledge in five main fields: extracellular and intracellular cell cycle deregulation, tumor immune microenvironment, tumor angiogenesis and hormones. RESULTS: EGFR immunohistochemical overexpression/gene amplification, representing early events in VSCC carcinogenesis, have been correlated with a worse prognosis and led to inclusion of erlotinib in cancer guidelines. p16 expression and HPV positivity are linked to a better prognosis, while p53 overexpression is linked to a worse prognosis; thus, biomarkers could help tailoring conventional treatment and follow-up. The implications of PD-L1 positivity in reference to HPV status and prognosis are still not clear, even though pembrolizumab is part of available systemic therapies. The role of tumor angiogenesis emerges through data on microvessel density, immunohistochemical VEGF staining and evaluation of serum VEGF concentrations. Few data exist on hormonal receptor expression, even though hormonal therapy showed great manageability. CONCLUSIONS: We suggest adding p16, p53 and HPV status to routine hystopathological examination of vulvar biopsies or surgical specimens. Predictive biomarkers for anti-EGFR and anti-PD-1/PD-L1 drugs are needed. Enough preclinical data supporting anti-angiogenic target therapies in clinical trials are existing. Hormonal receptor expression deserves further investigation.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/metabolismo , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Neoplasias Vulvares/etiologia , Neoplasias Vulvares/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Ciclo Celular/genética , Tomada de Decisão Clínica , Suscetibilidade a Doenças , Espaço Extracelular/metabolismo , Feminino , Humanos , Espaço Intracelular/metabolismo , Terapia de Alvo Molecular , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Neoplasias Vulvares/tratamento farmacológico , Neoplasias Vulvares/patologia
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