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1.
Medicine (Baltimore) ; 98(38): e17225, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567982

RESUMO

The present study is to analyze the difference of gene methylation in early cervical adenocarcinoma and to find molecular markers for predicting the occurrence and development of cervical adenocarcinoma.A total of 15 cases of primary cervical adenocarcinoma and 10 cases of primary cervical squamous cell carcinoma at stages IB1 or IIA1 were included in the study. Infinium MethylationEPIC BeadChip (850K) was used to screen specifically expressed genes in cervical adenocarcinoma tissues. Bisulfite sequencing polymerase chain reaction (BSP) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to verify the methylation levels in cervical adenocarcinoma, cervical squamous cell carcinoma, and normal cervical tissues.Sex determining region Y-box 1 (SOX1) and cyclin D1 (CCND1) genes participated in multiple signaling pathways, being the central nodes of gene regulatory networks. SOX1 gene, but not CCND1 gene, was a specifically methylated gene in cervical adenocarcinoma according to BSP. According to qRT-PCR, methylation level of SOX1 in cervical adenocarcinoma tissues is significantly different from that in cervical squamous cell carcinoma tissues or normal cervical tissues, and the methylation level of CCND1 in cervical adenocarcinoma tissues or cervical squamous cell carcinoma tissues is significantly different from that in normal cervical tissues.The present study demonstrates that tumor-suppressor gene SOX1 is a methylation-specific expression gene of cervical adenocarcinoma and is expected to become a specific molecular marker for the diagnosis of cervical adenocarcinoma. However, CCND1 gene was not proven to be a specific methylation expression gene in cervical adenocarcinoma in the present study.


Assuntos
Adenocarcinoma/genética , Metilação de DNA/genética , Fatores de Transcrição SOXB1/genética , Neoplasias do Colo do Útero/genética , Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Colo do Útero/metabolismo , Ciclina D1/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/genética , Marcadores Genéticos/genética , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Neoplasias do Colo do Útero/metabolismo
2.
Pol J Pathol ; 70(2): 84-90, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556558

RESUMO

The purpose of the study is to investigate the clinicopathological and prognostic features of dual hypoxia-inducible factor 1a (HIF-1a) and vascular endothelial growth factor (VEGF) expression in oesophageal squamous cell carcinoma (OSCC) patients. A total of 73 patients were enrolled in this study. The positive expression of HIF-1a was identified in 69.9% of the cases. Hypoxia-inducible factor 1a expression was correlative with pT (p = 0.008) and pTNM stage (p = 0.002). The positive expression of VEGF was identified in 63.0% of the cases. Vascular endothelial growth factor expression was correlative with pT (p = 0.005), pN (p = 0.045), and pTNM stage (p < 0.05). HIF-1a and VEGF expressions had a significantly positive correlation (p = 0.010). Dual positive expression of HIF-1a and VEGF was identified in 50.7% (37/73) of the cases, and it was significantly correlative with pT (p = 0.025), pN (p = 0.008), and pTNM stage (p = 0.014). The OSCC patients' 5-year survival rate was correlative with pT (p < 0.05), pN (p < 0.01), pTNM stage (p < 0.01), VEGF expression (p < 0.01), and dual expressions of HIF-1a and VEGF (p < 0.01). Cox regression analysis showed that pN and dual HIF-1a and VEGF expression were independent prognostic factors for the 5-year survival rate of the patients. In conclusion, HIF-1a combined with VEGF could enable us to more accurately predict the prognosis of OSCC patients.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Neoplasias Esofágicas/diagnóstico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Humanos , Prognóstico
3.
Life Sci ; 235: 116798, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472149

RESUMO

Lung cancer is the leading cause for cancer death due to refractory nature to current treatment strategies, understanding the regulatory mechanism of therapy resistance of lung cancer is important for lung cancer therapy. Here, we aimed to study the role of SHCBP1 in lung cancer cisplatin resistance, we found SHCBP1 was upregulated in lung cancer tissues and cells, patients with high SHCBP1 had poor prognosis. SHC binding and spindle associated 1 (SHCBP1) overexpression promoted cisplatin induced apoptosis resistance, migration and invasion determined by apoptosis assay and transwell assay with or without Matrigel, while SHCBP1 knockdown inhibited cisplatin induced apoptosis resistance, migration and invasion. Wnt pathway promoted lung cancer progression, we found SHCBP1 activated Wnt pathway, characterized by promoting ß-catenin nuclear translocation. Inhibition of Wnt pathway in SHCBP1 overexpression cells reversed the effect of SHCBP1 overexpression, confirming SHCBP1 promoted lung cancer progression through activating Wnt pathway. We also found SHCBP1 expression was positively corrected with Wnt pathway activity in lung cancer samples. In summary, we found SHCBP1 promoted cisplatin induced apoptosis resistance, migration and invasion through activating Wnt pathway, providing a potential target for lung cancer therapy.


Assuntos
Apoptose , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/patologia , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Invasividade Neoplásica , Prognóstico , Proteínas Adaptadoras da Sinalização Shc/genética , Taxa de Sobrevida , Proteínas Wnt/genética , Via de Sinalização Wnt , beta Catenina/genética
4.
J Cancer Res Clin Oncol ; 145(11): 2663-2674, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31541338

RESUMO

BACKGROUND: It is known that there are insufficient prognostic factors for non-small cell lung cancer (NSCLC). It was reported that PD-L1 was a prognostic factor for NSCLC,and c-Myc regulated the expression of PD-L1. Herein, we investigated c-Myc and PD-L1 expression and their association with overall survival (OS) in NSCLC. METHODS: Formalin-fixed paraffin-embedded specimens were obtained from 128 patients with surgically resected primary NSCLC. Immunohistochemistry was used to assess the expression of PD-L1 and c-Myc in this study. Pearson's Chi squared test or Fisher's exact test was used to analyze the correlation of the expression of PD-L1 and c-Myc with clinicopathologic features. The relationship between OS and the expression of PD-L1 and c-Myc was evaluated by the Kaplan-Meier method and Cox proportional hazards model, respectively. RESULTS: Positive expression of PD-L1 was detected in 59 patients (46.1%). Patients with negative expression of PD-L1 had remarkably longer OS than those with positive expression of PD-L1. The positive expression rate of c-Myc in NSCLC accounted for 58.6% (75/128) and its expression was significantly more frequent in males (p = 0.002) and patients with lymph node metastasis (p = 0.029). PD-L1 expression was positively correlated with c-Myc expression (r = 0.459, p < 0.001). The PD-L1 and c-Myc double-positive group had a worse prognosis than other subgroups (p < 0.05), and the PD-L1 and c-Myc double-negative group had a better OS than other subgroups (p < 0.05). CONCLUSION: Conjoint analysis of the expression of PD-L1 and c-Myc was a better prognostic approach for NSCLC patients.


Assuntos
Adenocarcinoma/secundário , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/secundário , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-myc/genética , Taxa de Sobrevida
5.
J Cancer Res Clin Oncol ; 145(9): 2285-2292, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31372722

RESUMO

BACKGROUND: The cell adhesion molecule close homologue of L1 (CHL1) is a potential tumour suppressor and was recently detected in non-small cell lung cancer (NSCLC) specimens. The expression pattern, prognostic, and functional role of CHL1 in NSCLCs is unknown. METHODS: We evaluated the protein expression of CHL1 by immunohistochemistry in 2161 NSCLC patients based on a tissue microarray. The results were correlated with clinical, histopathological, and patient survival data (Chi square test, t test, and log-rank test, respectively). A multivariate analysis (Cox regression) was performed to validate its impact on patients' survival. RESULTS: CHL1 was expressed in NSCLC patients and was significantly overexpressed in lung adenocarcinomas and squamous cell carcinomas compared to neuroendocrine and large cell carcinomas of the lung (p < 0.001). CHL1 expression was associated with the T stage in adenocarcinomas (p = 0.011) and with metastatic lymph node status and UICC stage in squamous cell carcinomas (p = 0.034 and p = 0.035, respectively). Increased CHL1 expression was associated with improved survival in univariate (p = 0.031) and multivariate analyses (odds ratio 0.797, 95% confidence interval 0.677-0.939, p = 0.007). CONCLUSION: The prognostic significance of CHL1 makes it a potential prognostic and therapeutic target and underlines its role as a tumour suppressor. Further validation studies and functional analyses are needed to investigate its potential role in tumourigenesis and dissemination.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Moléculas de Adesão Celular/metabolismo , Neoplasias Pulmonares/mortalidade , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Análise Serial de Tecidos
6.
Gynecol Oncol ; 155(1): 151-160, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31375269

RESUMO

OBJECTIVE: Toll-like receptors constitute an important component of innate immune mechanism. HPV is a known etiological factor of cervical cancer and is known to interfere with the expression of TLRs and downstream signaling pathway. It remains poorly understood whether HPV modulates the expression of TLRs. Hence, understanding HPV mediated immune alterations might aid in identifying novel therapeutic targets. The aim was to study the relative gene expression of TLRs & downstream signaling pathway in cervical carcinoma. METHODS: Cervical squamous cell carcinoma (CSCC) and normal cervical tissues were obtained. Subsequent to HPV genotyping, mRNA expression profiling using PCR Array was performed. Protein expression of relevant genes with western blot was studied. Levels of cytokines in cervicovaginal washes were estimated using a Luminex multiplex platform. RESULTS: All cases of cervical cancer were HR-HPV positive and predominant subtype was HPV16 (71.1%). Significant TLR4 upregulation and TLR2,7 downregulation were observed in HR-HPV infected cervix. TLR4,7 demonstrated low expression in CSCC. Molecules from cancer allied pathways; RELA, AKT, CDKN2A, and MDM2 demonstrated upregulation in CSCC. Protein expression data corroborated with gene expression profile. A diminished level of Th1 cytokines TNF-α, IFN-É£, IL-17, and IL-12 was observed in CSCC. Significantly increased levels of IL-1ß, IL-6 and IL-2 were detected in HR-HPV infected cervix. Kaplan Meier curve demonstrated high TLR4 and low TLR7 expression was associated with poor prognosis. CONCLUSION: The study demonstrates the HPV mediated dampening of the innate immune response in CSCC and provides support for exploring potential TLR2, 7 agonists as an adjunct therapy in CSCC patients.


Assuntos
Carcinoma de Células Escamosas/virologia , Papillomavirus Humano 16/fisiologia , Infecções por Papillomavirus/virologia , Receptores Toll-Like/metabolismo , Neoplasias do Colo do Útero/virologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Regulação para Baixo , Feminino , Expressão Gênica , Humanos , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Receptores Toll-Like/biossíntese , Receptores Toll-Like/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo
7.
Nat Methods ; 16(9): 866-869, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31451765

RESUMO

Auxin-inducible degron technology allows rapid and controlled protein depletion. However, basal degradation without auxin and inefficient auxin-inducible depletion have limited its utility. We have identified a potent auxin-inducible degron system composed of auxin receptor F-box protein AtAFB2 and short degron miniIAA7. The system showed minimal basal degradation and enabled rapid auxin-inducible depletion of endogenous human transmembrane, cytoplasmic and nuclear proteins in 1 h with robust functional phenotypes.


Assuntos
Proteínas de Arabidopsis/metabolismo , Carcinoma de Células Escamosas/metabolismo , Ácidos Indolacéticos/farmacologia , Proteólise/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Neoplasias Cutâneas/metabolismo , Fatores de Transcrição/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Colesterol/metabolismo , Citoplasma/metabolismo , Células HEK293 , Humanos , Reguladores de Crescimento de Planta/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Células Tumorais Cultivadas
8.
Cancer Invest ; 37(8): 339-354, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31412717

RESUMO

Squamous cell carcinoma (SCC) of skin has no standard treatment regimen, resulting in recurrences/metastasis. Although, doxorubicin (Dox), an anthracycline antibiotic has demonstrated some degree of efficacy. Molecular imaging can help in assessment of treatment response and prognosis of SCCs. MRI data showed that spin-spin relaxation (T2) time was longer (138 ± 2 msec) in Dox treated Test-II and there is no significant difference in spin-lattice relaxation (T1) time with respective controls. These findings further corroborated with the histology, proliferation index, apoptotic index, and HMGA1 protein expression. Thus, MRI may be a useful tool for monitoring treatment response noninvasively for skin tumor prognosis.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Doxorrubicina/farmacologia , Imagem por Ressonância Magnética , Imagem Molecular/métodos , Neoplasias Cutâneas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proteínas HMGA/genética , Proteínas HMGA/metabolismo , Camundongos , Valor Preditivo dos Testes , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Tempo , Carga Tumoral/efeitos dos fármacos
9.
Chem Biol Interact ; 312: 108799, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31433961

RESUMO

Black seed (Nigella sativa) oil has been used in various dermatological applications, and its major constituent, thymoquinone (TQ) has been shown to exhibit antiproliferative activity against various cancer cells. In this study, we tried to provide a mechanistic basis of apoptosis induced by TQ. Skin squamous carcinoma A431 cells were treated with TQ to monitor the apoptosis induced by TQ. Western blot analysis was performed to detect expression of apoptotic or anti-apoptotic proteins. Cell viability and apoptosis were measured by using the MTT test and FACS analysis, respectively. The induction of intracellular reactive oxygen species (ROS) by TQ was evaluated by 2',7'-dichlorofluorescein diacetate staining. In vivo xenograft study was followed to confirm the antiproliferative effect of TQ. Treatment of A431 cells with TQ-induced apoptosis, which was associated with the induction of p53 and Bax, inhibition of Mdm2, Bcl-2, and Bcl-xl expression, and activation of caspase-9, -7, and -3. TQ inhibited the constitutive phosphorylation and DNA binding activity of signal transducer and activator of transcription-3 (STAT3) in A431 cells by blocking the phosphorylation of the upstream kinase, Src. Moreover, the expression of STAT3 target gene products, cyclin D1 and survivin, was attenuated by TQ treatment. The generation of ROS was increased during TQ-induced apoptosis, and the pretreatment of N-acetyl cysteine, a ROS scavenger, reversed the apoptotic effect of TQ. In vivo study with NOD scid gamma (NSG) mice confirmed the inhibitory effect of TQ on the growth of A431 cells. Our results provide the first demonstration that TQ induces the apoptosis of A431 cells through generation of ROS and inhibition of STAT3 signaling.


Assuntos
Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Regulação para Baixo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Antineoplásicos/uso terapêutico , Benzoquinonas/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos NOD , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transplante Heterólogo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
10.
Cancer Invest ; 37(7): 288-292, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31319725

RESUMO

The proportion of anal cancer cases that produce elevated carcinoembryonic antigen (CEA) levels is not well described in the medical literature. In this study, we used electronic health record data from a single urban cancer center to identify patients from 2004-2018 with anal cancer who have also had a pre-initial treatment CEA measurement. We identified 40 patients who met our eligibility criteria. Of those, 11 (27.5%) had an elevated pretreatment CEA. Elevated CEA was not associated with any of the clinical or demographic covariates; however, three out of five patients with a recurrence had an elevated CEA.


Assuntos
Neoplasias do Ânus/metabolismo , Antígeno Carcinoembrionário/sangue , Carcinoma de Células Escamosas/metabolismo , Neoplasias do Ânus/patologia , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Regulação para Cima
11.
Arkh Patol ; 81(3): 12-18, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31317926

RESUMO

OBJECTIVE: To identify the expression of the molecular markers p53 and p16INK4A in head and neck squamous cell carcinoma (HNSCC) and to assess their impact on its clinical and morphological characteristics and overall survival (OS) rates in patients with HNSCC. MATERIAL AND METHODS: Histological blocks were immunohistochemically studied using anti-p16 and p53 monoclonal antibodies in Krasnodar Clinical Oncology Dispensary One in 2011 to 2016. Overexpression of p16INK4A was established in the presence of 3 and 4 staining points (nuclear and/or cytoplasmic staining in 40% or more tumor cells). That of p53 was determined in the presence of nuclear staining (3+) in more than 50% of tumor cells. RESULTS: Overexpression of p16 was found in 15 (27%) patients (9 (60%) men and 6 (40%) women). The p16-positive tumor status was associated with the female sex (p=0.023), which was characteristic of tonsil cancer (p<0.001) and represented by the nonkeratinizing type (p=0.008). Overexpression of p16 was associated with more frequent regional lymph node metastases (p=0.029). Overexpression of p53 was related to G2 tumor (p=0.021) and expression of p53 was less than 50% associated with tongue body cancer (p=0.004). Kaplan-Meier analysis showed that the 3-year OS in p16-positive HNSCC patients was significantly higher than that in p16-negative ones (p=0.048). Significantly higher OS rates were observed in p16-positive HNSCC patients than in p16INK4A-negative ones for Stage III-IV (p=0.021). OS rates in HNSCC patients with co-expression of p16INK4A (3 and 4 points) and p53 (3+) were significantly higher than in the absence of a combination of these molecular markers (p=0.049). At the same time, OS in HNSCC patients with co-expression of p16INK4A (3 and 4 points), p53 (3+) was significantly higher than in the absence of a set of these molecular markers for stage III-IV (p=0.01). OS in patients with Stages I-II HNNSCC and co-expression of p16INK4A (3 and 4 points) and p53 (3+) did not significantly differ from that in the absence of a set of these molecular markers (p=0.960). CONCLUSION: Overexpression of p16INK4A (3 and 4 points) can be used as a prognostic marker to divide patients into subgroups with different clinical and morphological characteristics. The data on the correlation of p53 overexpression as a marker of mutations in the TP53 gene are contradictory and the study has not revealed the worst overall survival rates. A set of markers for the expression of p16 (≥40%) and p53 (≥50%) has been proposed for use as a favorable prognostic sign.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas , Inibidor p16 de Quinase Dependente de Ciclina , Genes p53 , Neoplasias de Cabeça e Pescoço , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Células Epiteliais , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Prognóstico , Proteína Supressora de Tumor p53/metabolismo
12.
Life Sci ; 232: 116679, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31340168

RESUMO

AIMS: Amplified in liver cancer 1 gene (ALC1), a recently identified oncogene, was reported to be overexpressed in esophageal cancer cell lines and identified as a target oncogene in esophageal cancer pathogenesis. However, little literature is available to illustrate its significance in cisplatin resistance of esophageal squamous cell carcinoma (ESCC) cells. The aim of the current study was to investigate the effect of ALC1 on cisplatin cytotoxicity of ESCC cells and to study the potential mechanisms. MAIN METHODS: ALC1 at mRNA and protein levels were detected by qRT-PCR and western blot, respectively. Cell viability was evaluated using CCK-8 assay. Apoptosis was assessed using caspase-3/7 activity assay and flow cytometry analysis. Glycolysis level was evaluated by measuring glucose consumption and lactate production. The protein levels of p-protein kinase B (Akt) and Akt were determined by western blot. KEY FINDINGS: ALC1 was highly expressed in ESCC cells compared with human normal esophageal epithelial Het-1A cells. ALC1 knockdown suppressed the viability, induced apoptosis and enhanced cisplatin cytotoxicity in ESCC cells. In addition, ALC1 knockdown inhibited glycolysis and inactivated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in ESCC cells. Mechanistically, activation of the PI3K/Akt pathway by 740Y-P blocked the effects of ALC1 knockdown on cisplatin cytotoxicity and glycolysis in ESCC cells. In contrast, inhibition of the PI3K/Akt pathway by LY294002 or glycolysis by 2-deoxyglucose resisted the effect of ALC1 overexpression on cisplatin cytotoxicity in ESCC cells. SIGNIFICANCE: ALC1 knockdown enhanced cisplatin cytotoxicity of ESCC cells by inhibition of glycolysis through inactivation of the PI3K/Akt pathway.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/patologia , Cisplatino/farmacologia , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Neoplasias Esofágicas/patologia , Técnicas de Silenciamento de Genes , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apoptose , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/metabolismo , Ativação Enzimática , Neoplasias Esofágicas/enzimologia , Neoplasias Esofágicas/metabolismo , Glicólise , Humanos , Células Tumorais Cultivadas
13.
J Cancer Res Clin Oncol ; 145(9): 2241-2250, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31342168

RESUMO

PURPOSE: The tripartite motif (TRIM)16 acts as a tumour suppressor in both squamous cell carcinoma (SCC) and melanoma. TRIM16 is known to be secreted by keratinocytes, but no studies have been reported yet to assess the relationship between TRIM16 keratinocyte expression and melanoma development. METHODS: To study the role of TRIM16 in skin cancer development, we developed a keratinocyte TRIM16-specific knockout mouse model, and used the classical two-stage skin carcinogenesis challenge method, to assess the loss of keratinocyte TRIM16 on both papilloma, SCC and melanoma development in the skin after topical carcinogen treatment. RESULTS: Heterozygous, but not homozygous, TRIM16 knockout mice exhibited an accelerated development of skin papillomas and melanomas, larger melanoma lesions and an increased potential for lymph node metastasis. CONCLUSION: This study provides the first evidence that keratinocyte loss of the putative melanoma tumour suppressor protein, TRIM16, enhances melanomagenesis. Our data also suggest that TRIM16 expression in keratinocytes is involved in cross talk between keratinocytes and melanocytes, and has a role in melanoma tumorigenesis.


Assuntos
Proteínas de Transporte/genética , Queratinócitos/metabolismo , Perda de Heterozigosidade/fisiologia , Linfonodos/metabolismo , Melanócitos/metabolismo , Melanoma/genética , Neoplasias Cutâneas/genética , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proteínas de Transporte/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Queratinócitos/patologia , Linfonodos/patologia , Metástase Linfática , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Knockout , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
14.
Anticancer Res ; 39(7): 3757-3765, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262902

RESUMO

BACKGROUND/AIM: The study focused on identifying the mechanisms or drugs that might sensitize resistant KBV20C human oral squamous carcinoma cells overexpressing P-glycoprotein (P-gp) to antimitotic drug treatment. MATERIALS AND METHODS: Five HIV protease inhibitors (atazanavir, nelfinavir, darunavir, lopinavir, and ritonavir) were tested to identify drugs that could be used at a relatively low dose for sensitizing antimitotic drug-resistant KBV20C cells. Fluorescence-activated cell sorting, annexin V analyses, and rhodamine uptake tests were performed to further investigate the mechanism of action. RESULTS: Co-treatment with nelfinavir or lopinavir had a high sensitizing effect on vincristine-treated KBV20C cells. Nelfinavir and lopinavir reduced cell viability, increased G2 phase arrest, and up-regulated apoptosis when used as a co-treatment with vincristine. We also demonstrated that eribulin co-treatment with nelfinavir and lopinavir similarly increased sensitization of KBV20C cells. Only lopinavir was found to have a high P-gp-inhibitory activity (similar to verapamil). Interestingly, nelfinavir had very low P-gp-inhibitory activity, suggesting that vincristine-nelfinavir sensitization is independent of the P-gp-inhibitory effect of nelfinavir. We also demonstrated this same combination mainly caused sensitization due to late apoptosis in P-gp-overexpressing drug-resistant KBV20C cells. CONCLUSION: Highly antimitotic drug-resistant KBV20C cells can be sensitized by co-treatment with the repositioned HIV protease inhibitors nelfinavir and lopinavir. In particular, the sensitizing effect of co-treatment with nelfinavir on antimitotic drug-resistant cancer cells was found to be strong and independent of P-gp-inhibitory activity. As P-gp inhibition can be toxic to normal cells, selecting nelfinavir may be safer for normal cells in patients with drug-resistant cancer.


Assuntos
Antimitóticos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Furanos/farmacologia , Inibidores da Protease de HIV/farmacologia , Cetonas/farmacologia , Lopinavir/farmacologia , Nelfinavir/farmacologia , Vincristina/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Flufenazina/farmacologia , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Ritonavir/farmacologia
15.
DNA Cell Biol ; 38(7): 678-687, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31188017

RESUMO

Staging and pathological grading systems are convenient, but imperfect predictors of recurrence of head and neck squamous cell carcinoma. Therefore, to identify potential alternative prognostic markers, we investigated the methylation status of the promoter of Sal-like protein 2 (SALL2). SALL2 mRNA expression was absent in 8/9 (88.9%) University of Michigan squamous cell carcinoma cell lines, whereas two nonmalignant cell lines had stable expression. The normalized methylation value of SALL2 in cancer cell lines was significantly higher than in normal cell lines. SALL2 methylation found in 74 of 233 (31.8%) tumor specimens was correlated with the methylation status of both SALL1 and SALL3. SALL2 methylation was not associated with any difference in disease-free survival (DFS). Therefore, the presence of SALL2 methylation was statistically correlated with a decrease in DFS in patients with oral cancer (log-rank test, p = 0.032). Furthermore, it was associated with disease recurrence in 36.2% of oral cancer cases, with an odds ratio of 2.922 (95% confidence interval = 1.198-7.130; p = 0.018) by multivariate Cox proportional hazard regression analysis. This study suggests that cytosine-phosphate- guanosine (CpG) hypermethylation is a likely mechanism of SALL2 inactivation and supports the hypothesis that SALL2 could serve as an important clinical risk assessment.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Metilação de DNA , Neoplasias Bucais/genética , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Fatores de Transcrição/metabolismo
16.
Cancer Sci ; 110(8): 2471-2484, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31187548

RESUMO

Endoplasmic reticulum stress (ERS) plays a key role in the pathogenesis and development of tumors and protects tumor cells from radiation damage and drug-induced stress. We previously demonstrated that EGFR confers radioresistance in human papillomavirus (HPV)-negative human oropharyngeal carcinoma by activating ERS signaling through PERK and IRE1α. In addition, PERK confers radioresistance by activating the inflammatory cytokine NF-κB. However, the effect of IRE1 on radiosensitivity has not yet been fully elucidated. Here, we clarified that IRE1 overexpression was associated with poor outcome in HPV-negative patients treated with radiotherapy (P = 0.0001). In addition, a significantly higher percentage of radioresistant HPV-negative patients than radiosensitive HPV-negative patients exhibited high IRE expression (66.7% vs 27.8%, respectively; P = 0.001). Silencing IRE1 and XBP1 increased DNA double-strand break (DSB) and radiation-induced apoptosis, thereby increasing the radiosensitivity of HPV-negative oropharyngeal carcinoma cells. IRE1-XBP1 silencing also inhibited radiation-induced IL-6 expression at both the RNA and protein levels. The regulatory effect of IRE1-XBP1 silencing on DNA DSB-induced and radiation-induced apoptosis was inhibited by pretreatment with IL-6. These data indicate that IRE1 regulates radioresistance in HPV-negative oropharyngeal carcinoma through IL-6 activation, enhancing X-ray-induced DNA DSB and cell apoptosis.


Assuntos
Endorribonucleases/metabolismo , Interleucina-6/metabolismo , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Tolerância a Radiação/fisiologia , Proteína 1 de Ligação a X-Box/metabolismo , Apoptose/fisiologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla , Proteínas de Ligação a DNA/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Humanos , NF-kappa B/metabolismo , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo
17.
Neoplasma ; 66(5): 839-846, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31167533

RESUMO

Overexpression of Sonic hedgehog (Shh) is associated with progression of several cancers. The expression of Shh in non-small cell lung cancer (NSCLC) has been reported with inconsistent results. Lung adenocarcinoma (LAC) and lung squamous cell carcinoma (LSCC) are two major subtypes of NSCLC, which have different genetic genotypes and clinical therapeutic options. The expression of Shh in specimen of patients with NSCLC has yet to be comprehensively determined according to histological subtypes. Shh expression level was determined in 167 NSCLC patients (56 LAC patients and 111 LSCC patients) by immunohistochemical assay (IHC) and disease-free survival and overall survival of patients were analyzed using the Kaplan-Meier method. Shh protein level in pleural effusion from patients with pneumonia or pleural empyema, tuberculosis, LAC and LSCC was measured with enzyme-linked immunoassay (ELISA). We found that Shh expression is increased in tumor tissues from both LAC and LSCC patients compared with the paired adjacent tissues, while Shh level is negatively correlated with tumor differentiation only in LSCC, LSCC patients containing higher-Shh expression have a poorer prognosis. Furthermore, Shh level is elevated in pleural effusion from LSCC patients compared with that of parapneumonic and LAC pleural effusion. Shh expression in tumor tissues or pleural effusion may represent a potential diagnostic and prognostic marker of LSCC patients, pleural effusion Shh may assist to distinguish between LAC and LSCC.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Proteínas Hedgehog/metabolismo , Neoplasias Pulmonares/metabolismo , Biomarcadores Tumorais/metabolismo , Humanos , Prognóstico
18.
Cell Physiol Biochem ; 53(1): 141-156, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31237760

RESUMO

BACKGROUND/AIMS: Previous research has indicated that the currently available histone deacetylase inhibitors (HDACis) are not effective as monotherapies against oral squamous cell carcinoma (OSCC). However, HDACis act synergistically with other therapeutic agents to exert significant antitumor activities. Thus, a strategy to develop chemotherapeutic agents by combining several active groups based on histone deacetylase (HDAC) into a single molecule as a conjugate that modulates multiple cellular pathways may be useful for the treatment of OSCC. METHODS: The novel inhibitor Roxyl-ZR was prepared by organic synthesis and its anticancer effects on OSCC were investigated by cell metabolism (n=5), colony formation (n=3), cell cycle (n=3), cell apoptosis (n=3), wound healing (n=3), transwell migration (n=3), and 5-bromo-2'-deoxyuridine staining (n=3) assays in vitro and in in vivo xenograft mice models (4 mice/group for subcutaneous xenograft and 3 mice/group for orthotopic xenograft ). The abundance of Ki67, Bcl-2, and p-STAT3 was detected by immunohistochemistry staining (n=4). Apoptotic cells in the tumor tissues of mice were detected by terminal deoxynucleotidyl transferase dUTP nickend labeling assay (n=3). The abundance of related proteins levels were evaluated by western blot (n=3). E-cadherin expression was detected by an immunofluorescence assay (n=3). RESULTS: Compared with the approved HDACi, conjugated Roxyl-ZR exhibited significantly higher antitumor effects in OSCC cells. Roxyl-ZR suppressed OSCC cell proliferation by inducing the reduction of S phase and inducing caspase-dependent apoptosis by down-regulating Bcl-2 expression. Moreover, Roxyl-ZR attenuated the epithelial-mesenchymal transition, which is closely associated with migration and invasion. In addition, Roxyl-ZR inhibited OSCC xenograft mice models and showed low toxicity. The mechanism underlying the Roxyl-ZR-enhanced sensitivity to HDACi may be attributed to the inhibition of key regulators of JAK1-STAT3 signaling pathway. CONCLUSION: HDAC-cyclin-dependent kinase conjugates represent a novel approach to the development of OSCC treatment. Our findings may open a new avenue for the development of novel inhibitors for the treatment of OSCC.


Assuntos
Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Benzimidazóis/síntese química , Benzimidazóis/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Janus Quinase 1/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo
19.
Int J Mol Sci ; 20(9)2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035650

RESUMO

Citrate is a key intermediate of the tricarboxylic acid cycle and acts as an allosteric signal to regulate the production of cellular ATP. An elevated cytosolic citrate concentration inhibits growth in several types of human cancer cells; however, the underlying mechanism by which citrate induces the growth arrest of cancer cells remains unclear. The results of this study showed that treatment of human pharyngeal squamous carcinoma (PSC) cells with a growth-suppressive concentration of citrate caused cell cycle arrest at the G2/M phase. A coimmunoprecipitation study demonstrated that citrate-induced cell cycle arrest in the G2/M phase was associated with stabilizing the formation of cyclin B1-phospho (p)-cyclin-dependent kinase 1 (CDK1) (Thr 161) complexes. The citrate-induced increased levels of cyclin B1 and G2/M phase arrest were suppressed by the caspase-3 inhibitor Ac-DEVD-CMK and caspase-3 cleavage of mutant p21 (D112N). Ectopic expression of the constitutively active form of protein kinase B (Akt1) could overcome the induction of p21 cleavage, cyclin B1-p-CDK1 (Thr 161) complexes, and G2/M phase arrest by citrate. p85α-phosphatase and tensin homolog deleted from chromosome 10 (PTEN) complex-mediated inactivation of Akt was required for citrate-induced G2/M phase cell cycle arrest because PTEN short hairpin RNA or a PTEN inhibitor (SF1670) blocked the suppression of Akt Ser 473 phosphorylation and the induction of cyclin B1-p-CDK1 (Thr 161) complexes and G2/M phase arrest by citrate. In conclusion, citrate induces G2/M phase arrest in PSC cells by inducing the formation of p85α-PTEN complexes to attenuate Akt-mediated signaling, thereby causing the formation of cyclin B1-p-CDK1 (Thr 161) complexes.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Ácido Cítrico/farmacologia , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias Faríngeas/metabolismo , Proteína Quinase CDC2/genética , Proteína Quinase CDC2/metabolismo , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Ciclina B1/metabolismo , Humanos , Modelos Biológicos , Complexos Multiproteicos/metabolismo , Neoplasias Faríngeas/genética , Fosforilação , Transdução de Sinais
20.
Biomed Res Int ; 2019: 2807123, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080815

RESUMO

Cervical cancer is a life-threatening complication, appearing as the uncontrolled growth of abnormal cells in the lining of the cervix. Every year, increasing numbers of cervical cancer cases are reported worldwide. Different identification strategies were proposed to detect cervical cancer at the earlier stages using various biomarkers. Squamous cell carcinoma antigen (SCC-Ag) is one of the potential biomarkers for this diagnosis. Nanomaterial-based detection systems were shown to be efficient with different clinical biomarkers. In this study, we have demonstrated strontium oxide-modified interdigitated electrode (IDE) fabrication by the sol-gel method and characterized by scanning electron microscopy and high-power microscopy. Analysis of the bare devices indicated the reproducibility with the fabrication, and further pH scouting on the device revealed that the reliability of the working pH ranges from 3 to 9. The sensing surface was tested to detect SCC-Ag against its specific antibody; the detection limit was found to be 10 pM, and the sensitivity was in the range between 1 and 10 pM as calculated by 3σ. The specificity experiment was carried out using major proteins from human serum, such as albumin and globulin. SCC-Ag was shown to be selectively detected on the strontium oxide-modified IDE surface.


Assuntos
Antígenos de Neoplasias/administração & dosagem , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Serpinas/administração & dosagem , Estrôncio/administração & dosagem , Neoplasias do Colo do Útero/diagnóstico , Antígenos de Neoplasias/metabolismo , Carcinoma de Células Escamosas/metabolismo , Colo do Útero/metabolismo , Eletrodos , Feminino , Humanos , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/metabolismo , Óxidos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Serpinas/metabolismo , Neoplasias do Colo do Útero/metabolismo
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