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1.
Int J Mol Sci ; 21(2)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963541

RESUMO

Nickel (Ni), which is a carcinogenic workplace hazard, increases the risk of lung cancer. Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional cytokine that is involved in both angiogenesis and metastasis, but its role in lung cancer is still not clear. In this study, we assessed the role of ANGPTL4 in lung carcinogenesis under nickel exposure and investigated the effects of the antidiabetic drug metformin on ANGPTL4 expression and lung cancer chemoprevention. Our results showed that ANGPTL4 is increased in NiCl2-treated lung cells in a dose- and time-course manner. The expression of ANGPTL4 and HIF-1α induced by NiCl2 were significantly repressed after metformin treatment. The downregulation of HIF-1α expression by ROS savenger and HIF-1α inhibitor or knockdown by lentiviral shRNA infection diminished NiCl2-activated ANGPTL4 expression. Chromatin immunoprecipitation and the luciferase assay revealed that NiCl2-induced HIF-1α hypoxia response element interactions activate ANGPTL4 expression, which is then inhibited by metformin. In conclusion, the increased presence of ANGPTL4 due to HIF-1α accumulation that is caused by nickel in lung cells may be one mechanism by which nickel exposure contributes to lung cancer progression. Additionally, metformin has the ability to prevent NiCl2-induced ANGPTL4 through inhibiting HIF-1α expression and its binding activity. These results provide evidence that metformin in oncology therapeutics could be a beneficial chemopreventive agent.

2.
J Cancer ; 10(21): 5065-5069, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31602258

RESUMO

In Taiwan, the incidence rate of oral cancer is constantly increasing. Polymorphisms and lifestyle habits are major contributing factors to the development of oral cancer in such cases. Casein kinase 1 epsilon (CK1ε) gene expression plays a role in numerous cancers, and the knockdown of CK1ε induces tumor cell-selective cytotoxicity. The present study was designed to determine the effects of CK1ε gene polymorphisms combined with environmental carcinogens on susceptibility to developing oral squamous cell carcinoma and its clinicopathological status. Four single-nucleotide polymorphisms (SNPs) in CK1ε gene (rs135745, rs135764, rs1997644 and rs2075984) from 741 oral cancer patients and 462 healthy controls were analyzed using real-time polymerase chain reaction. Our results shown that variant types (GC) of CK1ε polymorphic rs135745 exhibited a significantly higher risk of 1.41 (95% confidence interval [CI]: 1.036-1.919) for oral cancer than did wild type alleles. Furthermore, these CK1ε gene SNPs along with betel-quid chewing and/or tobacco use further increased susceptibility to oral cancer. Moreover, variant genotypes (GC+CC) of CK1ε rs135745 were significantly associated with lymph node metastasis. These results suggested that the CK1ε gene polymorphism is associated with the clinicopathological development of oral cancer and increases individuals' susceptibility to environmental carcinogens (e.g., smoking and betel-quid chewing) in terms of developing oral cancer.

3.
J Cell Mol Med ; 23(11): 7699-7708, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31557402

RESUMO

ALPK1 is associated with chronic kidney disease, gout and type 2 diabetes mellitus. Raised renal ALPK1 level in patients with diabetes was reported. Accelerated fibrotic nephropathies were observed in hyperglycaemic mice with up-regulated ALPK1. The aim of this study was to identify the mediators contributing to ALPK1 effect involving in nephropathies induction. The haematoxylin and eosin staining, Masson's trichrome and immunohistochemical analysis of ALPK1, NFkB, CCL2 and CCL5 were performed in the mice kidney. Cytokine antibody array analysis was performed in streptozotocin-treated wild-type mice (WT-STZ) and streptozotocin-treated ALPK1 transgenic mice (TG-STZ). The ALPK1 levels were measured in mice kidney and in cultured cells. We found that the higher levels of renal CCL2/MCP-1, CCL5/Rantes and G-CSF expression in TG-STZ compared with the WT-STZ. Glucose increased ALPK1 expressions in monocytic THP1 and human kidney-2 cells. The protein expression of ALPK1, NFkB and lectin was up-regulated in glucose-treated HK-2 cells. Knockdown of ALPK1 reduced CCL2 and CCL5 mRNA levels, whereas overexpressed ALPK1 increased CCL2 and CCL5 in cultured kidney cells. Taken together, these results show that high glucose increases ALPK1 and chemokine levels in the kidney. Elevated ALPK1 expression enhances renal CCL2 and CCL5 expressions in vivo and in vitro. ALPK1 is a mediator for CCL2 and CCL5 chemokine up-regulation involving in diabetic nephropathies induction.

4.
Taiwan J Obstet Gynecol ; 58(5): 688-691, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31542094

RESUMO

OBJECTIVE: Uterine inversion is a rare postpartum complication. Non-puerperal uterine inversion is extremely rare. It mostly occurs with uterine tumors, especially leiomyoma. In most instances, the inversion may not be noticed until the time of surgery. The preoperative diagnosis is difficult. CASE REPORT: We report a case of non-puerperal complete uterine inversion that was initially diagnosed as cervical cancer. The uterine inversion was diagnosed preoperatively and she underwent total abdominal hysterectomy and bilateral salpingooophorectomy. The histological examination showed uterine hemangioma. CONCLUSION: Accurate diagnosis of the non-puerperal uterine inversion is important. Surgical intervention is necessary and it provides good prognosis. Hemangioma may be one of the causes of non-puerperal uterine inversion.


Assuntos
Hemangioma/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Inversão Uterina/diagnóstico , Neoplasias Uterinas/diagnóstico , Adulto , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Hemangioma/complicações , Humanos , Inversão Uterina/etiologia , Neoplasias Uterinas/complicações
5.
Front Oncol ; 9: 728, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440468

RESUMO

Potential function of UNC13C in variety of cancers including, oral squamous cell carcinoma (OSCC) remains obscure. In the present study, immunohistochemical staining in tissue microarrays containing 268 OSCC samples showed that UNC13C protein levels were inversely correlated with AJCC Stage III and IV (P = 0.002) and death (P = 0.0134). Patients with lower UNC13C expression had a significantly shorter survival (P = 0.0231) than those with higher UNC13C expression. We also identified decreased overall UNC13C expression in oral cancer cell lines. In addition, our functional analysis of UNC13C shows that overexpression of UNC13C inhibited migration and invasion capacities of SCC-9 and SAS cells compared with the empty plasmid transfected cells. Further experiments suggested that transcription factors (Slug, Snail, Twist, and ZEB1) and mesenchymal marker (Vimentin) were down regulated and Tight Junction Protein (Claudin1) was up regulated after UNC13C overexpression in SCC9 and SAS cells. The novel role of UNC13C is revealed for the first time in OSCC. In summary, these results suggest that UNC13C as a novel tumor suppressor and an essential regulator of EMT signaling pathway during OSCC progression, and thus it could be used as a target for preventing oral cancer metastasis.

6.
Cancer Manag Res ; 11: 5163-5169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239771

RESUMO

Purpose: c-MYC has been noted in many tumor types, but its functional significance and clinical utility in oral squamous cell carcinoma (OSCC) are not well known. Here we studied the expression of c-MYC in correlation to clinical outcome in patients with oral squamous cell carcinoma. Methods: The current study, using immunohistochemical staining, first examined c-MYC expression in OSCC patients and further correlated its expression with clinicopathological parameters. Results: c-MYC was expressed in the majority of OSCC patients (n=133). The c-MYC expression is associated with histological grade (P=0.0205) of patients with oral squamous cell carcinoma. Multivariate Cox regression analysis revealed that TN stage (P<0.001), American Joint Committee on Cancer (AJCC) stage (P<0.0001), and tumor differentiation (P=0.0025) were independent factors for overall survival in patients with OSCC except for c-MYC expression (P>0.05). Multiplicative-scale interaction between T stage (III/IV) and low c-MYC expression on mortality risk was identified (P=0.0233). Kaplan-Meier survival analysis demonstrated that oral cancer patients (T III/IV stage) with high c-MYC expression had better survival than those with low and medium c-MYC expression (P=0.0270). Conclusion: Our data indicate that c-MYC is a potential biomarker that can be used as a therapeutic target for treating OSCC patients with T stage (III/IV).

7.
Cancer Manag Res ; 11: 2589-2594, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114325

RESUMO

Introduction: Oral cancer is a prevalent form of cancer worldwide, particularly in Taiwan, and mechanisms involved in oral squamous cell carcinoma (OSCC) progression remain relatively unknown. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an oncoprotein, is aberrantly expressed in many human malignant tumors including oral cancer. However, the expression and role played by CIP2A in oral cancer pathogenesis remain obscure. Methods: In this study, immunohistochemistry was used to analyze CIP2A expression between OSCC tissues and their adjacent noncancerous tissues. Furthermore, associations between CIP2A expression and histopathological parameters were investigated. Results: In this study, we showed that CIP2A was overexpressed in most of the OSCC tissues. High CIP2A expression was significantly associated with moderate/poor tumor differentiation (P=0.02). No significant association was found between CIP2A expression and other clinical parameters. Kaplan-Meier analysis revealed that high CIP2A expression showed poorer survival rates than those with low CIP2A expression (P=0.047). Multivariate Cox regression analysis indicated that CIP2A expression, N stage, American Joint Committee on Cancer stage and clinical therapy were independent prognostic factors for survival. Conclusion: Thus, our study suggests that CIP2A is an independent prognostic marker for OSCC and a novel target for OSCC treatment.

8.
Acta Histochem ; 121(5): 628-637, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31133374

RESUMO

The identification of prognostic markers for colorectal cancer (CRC) has important clinical implications. However, the association between meningioma 1 (MN1) expression and clinical outcomes of CRC has not been fully investigated. The aim of this study was to investigate the expression of MN1 in the clinical context of CRC. We first used immunohistochemistry (IHC) staining to examine and compare MN1 expression between multiple human cancer tissues and normal tissues. Initial screening revealed that the expression of MN1 proteins was significantly higher in tumor tissues of the breast, colon, and liver than in normal tissues. In further testing conducted on 59 paired CRC samples, we observed that the expression of MN1 in CRC tissue samples was significantly higher than in adjacent normal tissues. Moreover, high MN1 expression was not significantly associated with clinicopathological characteristics. Kaplan-Meier survival analysis revealed that high expression of MN1 mRNA or MN1 protein was significantly associated with poor CRC prognosis. Furthermore, univariate Cox analysis revealed that a high MN1 score was significantly associated with prognostic factors. Multivariate Cox analysis further indicated that gender, histologic grade, tumor-node-metastasis (TNM) stage, and a high MN1 score were independent factors of overall CRC survival rates. Finally, MN1 and PCNA protein levels were positively correlated, which suggests that MN1 may be involved in the cell proliferation process during CRC formation. Our results, which confirm those of other studies, indicate that (1) high levels of MN1 expression contribute to poor CRC prognosis and (2) MN1 can serve as a novel potential biomarker in predicting the prognosis of CRC patients.


Assuntos
Neoplasias Colorretais/mortalidade , Proteínas Supressoras de Tumor/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Proteínas Supressoras de Tumor/genética
9.
PLoS One ; 14(1): e0210901, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30657779

RESUMO

A number of genetic variants were suggested to be associated with oral malignancy, few variants can be replicated. The aim of this study was to identify significant variants that enhanced personal risk prediction for oral malignancy. A total of 360 patients diagnosed with oral squamous cell carcinoma, 486 controls and 17 newly diagnosed patients with OPMD including leukoplakia or oral submucous fibrosis were recruited. Fifteen tagSNPs which were derived from somatic mutations were genotyped and examined in associations with the occurrence of oral malignancy. Environmental variables along with the SNPs data were used to developed risk predictive models for oral malignancy occurrence. The stepwise model analysis was conducted to fit the best model in an economically efficient way. Two tagSNPs, rs28647489 in FAT1 gene and rs550675 in COL9A1 gene, were significantly associated with the risk of oral malignancy. The sensitivity and specificity were 85.7% and 85.5%, respectively (area under the receiver operating characteristic curve (AUC) was 0.91) for predicting oral squamous cell carcinoma occurrence with the combined genetic variants, betel-quid, alcohol and age. The AUC for OPMD was only 0.69. The predictive probability of squamous cell carcinoma occurrence for genetic risk score without substance use increased from 10% up to 43%; with substance use increased from 73% up to 92%. Genetic variants with or without substance use may enhance risk prediction for oral malignancy occurrence in male population. The prediction model may be useful as a clinical index for oral malignancy occurrence and its risk assessments.


Assuntos
Caderinas/genética , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/genética , Colágeno Tipo IX/genética , Neoplasias Bucais/etiologia , Neoplasias Bucais/genética , Adulto , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Areca/efeitos adversos , Estudos de Casos e Controles , Feminino , Interação Gene-Ambiente , Humanos , Leucoplasia Oral/etiologia , Leucoplasia Oral/genética , Masculino , Pessoa de Meia-Idade , Fibrose Oral Submucosa/etiologia , Fibrose Oral Submucosa/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fumar/efeitos adversos
10.
J Cell Physiol ; 234(8): 13984-13993, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30624777

RESUMO

Areca nut has been evaluated as a group I carcinogen to humans. However, the exact compounds of areca nut causing oral cancer remain unproven. Previous findings from our lab revealed that arecoline N-oxide (ANO), a metabolite of arecoline, exhibits an oral fibrotic effect in immune-deficient NOD/SCID mice. The aim of this study is to investigate the oral potentially malignant disorders (OPMD) inductive activity between areca-alkaloid arecoline and its metabolite ANO in C57BL/6 mice. Our findings show that ANO showed higher activity in inducing hyperplasia with leukoplakia and collagen deposition in C57BL/6 mice compared with the arecoline treated groups. Importantly, immunohistochemical studies showed significant upregulation of NOTCH1, HES1, FAT1, PCNA, and Ki67 expressions in the pathological hyperplastic part. In addition, in vitro studies showed that upregulation of NOTCH1 and FAT1 expressions in ANO treated HGF-1 and DOK cell models. We found that NOTCH1 regulates TP53 expression from NOTCH1 knockdown oral cancer cells. The DNA damage was significantly increased after arecoline and ANO treatment. Further, we found that arecoline-induced H2AX expression was regulated by FMO3. Altogether, our findings show that ANO exhibited higher toxicity in OPMD activity and play a significant role in the induction of areca nut mediated oral tumorigenesis.


Assuntos
Arecolina/análogos & derivados , Caderinas/metabolismo , Carcinogênese/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Óxidos N-Cíclicos/farmacologia , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Receptor Notch1/metabolismo , Animais , Arecolina/farmacologia , Biomarcadores Tumorais/metabolismo , Peso Corporal/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperplasia , Antígeno Ki-67/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Neoplasias Bucais/genética , Proteínas de Neoplasias/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição HES-1/metabolismo , Regulação para Cima/efeitos dos fármacos
11.
Environ Toxicol ; 34(3): 233-239, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30431227

RESUMO

Glioblastoma (GBM) is the most mortality brain cancer in the world. Due to high invasion and drug resistance cause the poor prognosis of GBM. Naringenin, an ingredient of citrus, exhibits many cellular functions such as antioxidant, anti-inflammation, and anticancer. Naringenin inhibits the migration of bladder and lung cancer via modulation of MMP-2 and/or MMP-9 activities, Naringenin inhibits migration and trigger apoptosis in gastric cancer cells through downregulation of AKT pathway. However, the effects of naringenin in GBM still remain to be elucidated. In this study, we reveal the molecular mechanisms of naringenin in the inhibition of migration and invasion in GBM. No overt alternation of cell proliferation was found in of GBM 8901 cells treated with different concentration of naringenin. Slight decreased cell viability was found in GBM 8401 cell treated with 200 and 300 µM naringenin. Significant reduction of migration and invasion as assayed by Boyden chamber analysis was found in of GBM cells treated with 100, 200, and 300 µM naringenin. Zymography analysis also revealed that the activities of MMP-2 and MMP-9 of GBM cells were significantly inhibited in response to 100, 200, or 300 µM naringenin treatment. Proteins of MMP-2 and MMP-9 were downregulated in naringenin treated GBM cells. In addition, naringenin also attenuated the activities of ERK and p38. Naringenin decreased mesenchymal markers (snail and slug) expression as revealed by Western blot analysis. Taken together, our findings indicated that naringenin eliminated the migration and invasion of GBM cells through multiple mechanisms including inhibition of MMPs, ERK, and p38 activities and modulation of EMT markers. Our results also suggested that naringenin may be a potential agent to prevent metastasis of GBM.


Assuntos
Neoplasias Encefálicas/fisiopatologia , Movimento Celular/efeitos dos fármacos , Flavanonas/farmacologia , Glioblastoma/fisiopatologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica
12.
Am J Pathol ; 189(1): 190-199, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30315765

RESUMO

Oral squamous cell carcinoma (OSCC) is the most common malignant cancer, with high mortality rates in advanced stages. Recent studies have shown that the expression of ALPK1 mRNA and its inhibitory differentiation function are associated with cancer progression. However, the expression and clinicopathologic features of ALPK1 in OSCC remain unexplored. Herein, the authors investigated the expression patterns of ALPK1 in 39 matched OSCC patients and examined the relationship between ALPK1 protein expression and clinicopathologic factors using immunohistochemical scores. Using Western blot analysis, ALPK1 expression was found to be significantly higher in tumor tissues than that in nontumor tissues. Through an immunoreactive scoring system, a significantly higher number of advanced-stage tumor size T4 and lymph node metastasis N2 exhibited higher ALPK1 expression levels than that exhibited by T1/T2/T3 tumors and N0/N1. In addition, ALPK1 protein expression was aberrant in malignant oral cancer cell lines compared with that in pre-malignant oral epithelial cells, whereas minimal expression was observed in normal oral epithelial cells. Knockdown of ALPK1 resulted in a significant reduction in cell growth, migration, and invasion capacity in vitro. Consequently, expression of N-cadherin and vimentin decreased in ALPK1-deficient cells. Thus, these results suggest that ALPK1 serves as a potential biomarker and target for OSCC development in late stages.


Assuntos
Biomarcadores Tumorais/biossíntese , Carcinoma de Células Escamosas/enzimologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Proteínas Quinases/biossíntese , Neoplasias da Língua/enzimologia , Adulto , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos CD/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Caderinas/genética , Caderinas/imunologia , Caderinas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Humanos , Queratinócitos/imunologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Metástase Linfática/genética , Metástase Linfática/imunologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Estadiamento de Neoplasias , Proteínas Quinases/genética , Proteínas Quinases/imunologia , Neoplasias da Língua/genética , Neoplasias da Língua/imunologia , Neoplasias da Língua/patologia , Vimentina/genética , Vimentina/imunologia , Vimentina/metabolismo
13.
Endocr Pathol ; 29(4): 324-331, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30120715

RESUMO

Genetic and epigenetic alterations are associated with the progression and prognosis of medullary thyroid carcinoma (MTC). We performed whole-exome sequencing of tumor tissue from seven patients with sporadic MTC using an Illumina HiSeq 2000 sequencing system. We conducted Sanger sequencing to confirm the somatic mutations in both tumor and matched normal tissues. We applied Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis with the Database for Annotation, Visualization, and Integrated Discovery and STRING for pathway analysis. We detected new somatic mutations in the BICD2, DLG1, FSD2, IL17RD, KLHL25, PAPPA2, PRDM2, PSEN1, SCRN1, and TTC1 genes. We found a somatic mutation in the PDE4DIP gene that had previously been discovered mutated in other tumors but that had not been characterized in MTC. We investigated pathway deregulation in MTC. Data regarding 1152 MTCs were assembled from the Catalogue of Somatic Mutations in Cancer (COSMIC) and seven of our patients. Ontological analysis revealed that most of the variants aggregated in pathways that included the signaling pathways of thyroid cancer, central carbon metabolism, microRNAs in cancer, PI3K-Akt, ErbB, MAPK, mTOR, VEGF, and RAS. In conclusion, we conducted wide-ranging exome-wide analysis of the mutational spectrum of MTC in Taiwan's population and detected novel genes with potential associations with MTC tumorigenesis and irregularities in pathways that resulted in MTC pathogenesis.


Assuntos
Carcinoma Neuroendócrino/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias da Glândula Tireoide/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Taiwan , Adulto Jovem
14.
Biochem Biophys Res Commun ; 503(3): 1442-1449, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30029884

RESUMO

In this study, we investigated the expression of jumonji domain-containing 4 (JMJD4) in colon adenocarcinoma (CA) look for evidences for future studies on clinical diagnostic and prognostic value. The immunohistochemical (IHC) reactivity of JMJD4 was assessed in human tissue microarrays using monoclonal antibodies. An initial investigation revealed that the expression of JMJD4 protein was significantly higher in tumor tissue of the colon and liver than in normal tissue. Upon further investigation, we observed significant positivity of JMJD4 between 59 paired samples from CA tissue and adjacent normal tissue. JMJD4 protein expression in CA differed significantly according to the histological grade and M-class (distant metastasis). We also determined that the mRNA or protein expression of JMJD4 was significantly associated with poor survival in patients with CA. Finally, univariate and multivariate analysis revealed that JMJD4 expression could be a prognostic indicator for patients with CA and may provide a new target for the development of novel therapies for the treatment of CA.


Assuntos
Adenocarcinoma/genética , Neoplasias do Colo/genética , Oxigenases de Função Mista/genética , Adenocarcinoma/diagnóstico , Neoplasias do Colo/diagnóstico , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Oxigenases de Função Mista/análise , RNA Mensageiro/genética , Taxa de Sobrevida
15.
Cancer Biomark ; 22(4): 747-753, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29945346

RESUMO

BACKGROUND: Discoidin domain receptors (DDRs), a collagen receptor tyrosine kinase, play a major role in cancer progression. DDR2 has been suggested as a prognostic marker in several cancer types; however, the correlation between DDR2 expression and clinical outcome of oral cancer patients in Taiwan population has not been investigated. MATERIALS AND METHODS: In the present study we sought to determine the clinical significance of Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2) expression in oral squamous cell carcinoma (OSCC) patients. We examined DDR2 expression in OSCC specimens by immunohistochemistry and then we analyzed the association of DDR2 expression with clinicopathological factors in OSCC. RESULTS: We divided 254 OSCC cases into two groups based on DDR2 expression levels and compared with several clinicopathological factors and their overall survival. The group with high DDR2 expression had significantly higher frequencies of lymph node metastasis (P= 0.0094) and AJCC stage (P= 0.0058) compared to the group with low DDR2 expression. Furthermore, the lymph node metastasis oral cancer patients with high DDR2 expression had low survival rate than low DDR2 group (P= 0.0458). CONCLUSIONS: Our data indicate that DDR2 is a potent biomarker that can be used as an effective therapeutic target for treating OSCC patients with lymph node metastasis.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Receptor com Domínio Discoidina 2/genética , Neoplasias Bucais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfonodos/patologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia
16.
BMJ Open ; 8(6): e021385, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29934389

RESUMO

OBJECTIVE: Lung adenocarcinoma is a non-small cell lung cancer, a common cancer in both genders, and has poor clinical outcome. Our aim was to evaluate the role of epidermal growth factor (EGF)-like domain multiple 6 (EGFL6) and its prognostic significance in lung adenocarcinoma. METHODS: EGFL6 expression was studied by immunohistochemical staining of specimens from 150 patients with lung adenocarcinoma. The correlation between clinicopathological features and EGFL6 expression was quantitatively analysed. We used Kaplan-Meier analysis and Cox proportional hazard models to examine the prognostic value of EGFL6 in terms of overall survival. RESULTS: No significant correlation was found between EGFL6 expression and clinical parameters. However, patients with high levels of EGFL6 expression showed a tendency towards poor prognosis, with borderline statistical significance. Grouping the patients according to a medium age value revealed a significant association between high EGFL6 expression and poor clinical outcome in young patients. This finding was further confirmed by grouping the patients into three groups according to age. HR in patients with high EGFL6 expression was higher in younger patients than in older patients. CONCLUSION: High EGFL6 expression may serve as a marker for poor prognosis of lung adenocarcinoma, especially in younger patients.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Glicoproteínas de Membrana/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Idoso , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Taiwan/epidemiologia
17.
Int J Oncol ; 53(1): 417-433, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29750421

RESUMO

Long non­coding RNAs (lncRNAs) have various functions, including chromatin remodeling and the regulation of gene expression at the transcriptional and post-transcriptional levels. However, few lncRNAs have been investigated comprehensively, with the majority being uncharacterized. In the present study, a bioinformatics pipeline was established to identify novel lncRNA sequences similar to the 3'-untranslated regions (3'­UTRs) of protein-coding genes. These pairs of lncRNAs and coding genes contained the same microRNA (miRNA) target sites; the lncRNA CR933609 matched the 3'­UTR of INO80 complex subunit D (INO80D) mRNA. The expression levels of CR933609 and INO80D were significantly decreased in non­small cell lung cancer (NSCLC) and other cancer tissues. The expression levels of CR933609 and INO80D were decreased in CR933609-knockdown NSCLC cells, but only expression levels of INO80D decreased in INO80D knockdown cells. It was shown that there are independent promoters in CR933609 and INO80D. It was also found that the expression levels of INO80D were downregulated by endogenous miRNA­5096 in A549 cells, but not in CR933609-overexpressing A549 cells. Furthermore, the lncRNA CR933609 acted as a decoy to protect INO80D from downregulation by miRNA­5096 in NSCLC cells. A protocol was established to identify novel lncRNAs in the 3'­UTR and the existence of novel lncRNAs was confirmed.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Montagem e Desmontagem da Cromatina/genética , DNA Helicases/genética , RNA Longo não Codificante/genética , Regiões 3' não Traduzidas/genética , Células A549 , Carcinoma Pulmonar de Células não Pequenas/patologia , Biologia Computacional , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pulmonares , MicroRNAs/genética , Fases de Leitura Aberta/genética
18.
Hum Pathol ; 78: 151-158, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29753010

RESUMO

Among women in Taiwan, thyroid cancer is the fifth most common malignant neoplasia. However, genomic profiling of papillary thyroid cancer (PTC) cases from Taiwan has not been attempted previously. We used whole-exome sequencing to identify mutations in a cohort of 19 PTC patients. Sequencing was performed using the Illumina system; Sanger sequencing was used to validate all identified mutations. We identified new somatic mutations in APC, DICER1, LRRC8D and NDRG1. We also found somatic mutations in ARID5A, CREB3L2, MDM4, PPP2R5A and TFPT; mutations in these genes had been found previously in other tumors, but had not been described previously in PTC. We also investigated the pathway deregulation in BRAF-mutated PTC compared with wild-type BRAF PTC. In checking our gene mutations against The Cancer Genome Atlas (TCGA) database, we identified aberrations in one pathway that are specific to BRAF-mutated PTC: maturity-onset diabetes of the young. In addition, the caffeine metabolism pathway showed aberrations that are specific to wild-type BRAF PTC. For this study, we performed a comprehensive exome-wide analysis of the mutational spectra of Taiwanese patients with PTC. We identified novel genes that are potentially associated with PTC tumorigenesis, as well as aberrations in pathways that led to the distinct pathogeneses of BRAF-mutated PTC and wild-type BRAF PTC, which may provide a new target for PTC therapy.


Assuntos
Carcinoma Papilar/genética , Exoma/genética , Câncer Papilífero da Tireoide/genética , Sequenciamento Completo do Exoma , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Taiwan , Sequenciamento Completo do Exoma/métodos
19.
Clin Chim Acta ; 479: 66-71, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29305191

RESUMO

INTRODUCTION: Squamous cell carcinoma is the most common cancer of the oral cavity. In spite of advancements in surgical, chemoradiological and targeted therapies, these therapeutic strategies still have had little impact on survival rates. X-box binding protein-1 (XBP-1) is a potent transcription factor that is involved in the unfolded protein response (UPR) pathway, which itself is activated in response to endoplasmic reticulum stress as a method to restore cellular homeostasis. The role XBP-1 plays in oral squamous cell carcinoma (OSCC) has yet to be determined. In this study, we used molecular and immunohistochemical analyses to investigate the role of XBP-1 protein playing in the OSCC carcinogenesis. MATERIALS AND METHODS: We used immunohistochemical analyses to investigate XBP-1 expression in 255 OSCC tissue specimens, as well as migration and invasion assays with XBP-1 siRNA transfection of oral cancer cell lines to confirm its role in OSCC. RESULTS: The XBP-1 immunostaining was dichotomized as low-level expression and high-level expression. We found that low-level cytoplasmic XBP-1expression was significantly correlated with larger tumor size (p=0.047), more advanced clinical stage (p<0.0001), lymph node metastasis (p=0.002), and shorter overall survival (p=0.011). Kaplan-Meier survival curves showed that low-level cytoplasmic XBP-1 expression was significantly correlated with shorter overall survival (p=0.031). The univariate Cox regression analysis revealed that cytoplasmic XBP-1 expression was a prognostic factor for overall survival of patients with OSCC. We also found that inhibition of XBP-1 promoted OSCC cell migration and invasion. CONCLUSION: Our results suggest that XBP-1 expression may play an essential role in the pathogenesis of OSCC and that targeting XBP-1 may be a sound therapeutic strategy.


Assuntos
Carcinoma de Células Escamosas/genética , Citoplasma/genética , Neoplasias Bucais/genética , Proteína 1 de Ligação a X-Box/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Neoplasias Bucais/cirurgia , Reação em Cadeia da Polimerase , Prognóstico , RNA Interferente Pequeno/farmacologia , Análise de Sobrevida , Células Tumorais Cultivadas , Proteína 1 de Ligação a X-Box/antagonistas & inibidores
20.
J Cell Physiol ; 233(2): 1300-1311, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28516459

RESUMO

Protein phosphatase 2A (PP2A) is a tumor suppressor gene, that has been frequently deactivated in many types of cancer. However, its molecular and clinical relevance in oral squamous cell carcinoma (OSCC) remain unclear. Here we show that, PP2A deactivation is a common event in oral cancer cells and hyperphosphorylation in its tyrosine-307 (Y307) residue contributes to PP2A deactivation. PP2A restoration by FTY720 treatment reduced cell growth and decreased GSK-3ß phosphorylation without significantly altering other PP2A targets. We further detected PP2A phosphorylation in 262 OSCC tissues. Increased expression of p-PP2A in the tumor tissues was significantly correlated with higher N2/N3-stage (aOR = 2.1, 95%CI: 1.2-3.8). Patients with high p-PP2A expression had lower overall survival rates than those with low expression. Hazard ratio analysis showed that, high p-PP2A expression was significantly associated with mortality density (aOR = 2.2, 95%CI: 1.2-4.0) and lower 10-year overall survival (p = 0.027) in lymph node metastasis. However, no interaction was observed between p-PP2A expression and lymph node metastasis. All our results suggest that PP2A is frequently deactivated in oral cancer and determines poor outcome, restoring its expression by FTY720 can be an alternative therapeutic approach in OSCC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Cloridrato de Fingolimode/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Proteína Fosfatase 2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ativação Enzimática , Ativadores de Enzimas/farmacologia , Feminino , Glicogênio Sintase Quinase 3 beta/metabolismo , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/enzimologia , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Análise Multivariada , Estadiamento de Neoplasias , Razão de Chances , Fosforilação , Modelos de Riscos Proporcionais , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Fatores de Tempo , Tirosina
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