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1.
Hum Pathol ; 112: 1-8, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33741347

RESUMO

Loss of SMARCB1 protein expression has recently been identified in a variety of tumor types such as poorly differentiated chordoma (PCh) and malignant rhabdoid tumor (MRT) including atypical teratoid/rhabdoid tumor (AT/RT). PCh is characterized by poorly differentiated epithelioid tumor cells, sheet arrangement, and coexpression of nonepithelial and epithelial markers. Rhabdoid cells are sometimes present. Therefore, the differentiation of these tumors is often difficult. Brachyury is a transcription factor within the T-box family typically expressed in notochord tissue and chordomas. Some studies have reported high specificity and sensitivity of brachyury expression in chordomas. In the present study, we analyzed immunohistochemical brachyury expression in SMARCB1-deficient tumors and discuss important clinicopathological and diagnostic points, especially in cases of intracranial SMARCB1-deficient tumors with brachyury expression. Brachyury and cytokeratin immunoexpression status was examined in 42 formalin-fixed paraffin-embedded SMARCB1-deficient tumor specimens (PCh, 6 cases; extra-central nervous system [CNS] MRT, 26 cases; AT/RT, 10 cases) and 25 cases of conventional chordoma (CCh). All cases of PCh and CCh showed diffuse immunopositivities for cytokeratin 8, pan-cytokeratin, and brachyury. Brachyury immunoexpression was present in 2 extra-CNS MRT (8%) and 5 AT/RT (50%) cases, but immunopositivity was focal not diffuse. Indeed, in almost all cases of AT/RT (cytokeratin 8, 7/10 cases; pan-cytokeratin, 7/10 cases) and extra-CNS MRT (cytokeratin 8, 23/26 cases; pan-cytokeratin, 25/26 cases), fewer than 50% of cells showed immunoreactivity. Although the histological and clinical features of PCh resemble those of AT/RT, semiquantitative evaluations of the degree of brachyury and cytokeratin immunoexpressivity may help to distinguish PCh from AT/RT.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/diagnóstico , Cordoma/diagnóstico , Proteínas Fetais/biossíntese , Tumor Rabdoide/diagnóstico , Proteínas com Domínio T/biossíntese , Teratoma/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Cordoma/metabolismo , Cordoma/patologia , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Proteína SMARCB1/deficiência , Teratoma/metabolismo , Teratoma/patologia
2.
Neurotherapeutics ; 17(4): 2015-2027, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32785847

RESUMO

Glioblastomas (GBMs) are the most aggressive tumor type of the central nervous system, mainly due to their high invasiveness and innate resistance to radiotherapy and chemotherapy, with temozolomide (TMZ) being the current standard therapy. Recently, brachyury was described as a novel tumor suppressor gene in gliomas, and its loss was associated with increased gliomagenesis. Here, we aimed to explore the role of brachyury as a suppressor of glioma invasion, stem cell features, and resistance to TMZ. Using gene-edited glioma cells to overexpress brachyury, we found that brachyury-positive cells exhibit reduced invasive and migratory capabilities and stem cell features. Importantly, these brachyury-expressing cells have increased expression of differentiation markers, which corroborates the results from human glioma samples and in vivo tumors. Glioma cells treated with retinoic acid increased the differentiation status with concomitant increased expression of brachyury. We then selected TMZ-resistant (SNB-19) and TMZ-responsive (A172 and U373) cell lines to evaluate the role of brachyury in the response to TMZ treatment. We observed that both exogenous and endogenous brachyury activation, through overexpression and retinoic acid treatment, are associated with TMZ sensitization in glioma-resistant cell lines. In this study, we demonstrate that brachyury expression can impair aggressive glioma features associated with treatment resistance. Finally, we provide the first evidence that brachyury can be a potential therapeutic target in GBM patients who do not respond to conventional chemotherapeutic drugs.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proteínas Fetais/biossíntese , Glioma/metabolismo , Proteínas com Domínio T/biossíntese , Temozolomida/uso terapêutico , Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proteínas Fetais/genética , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Proteínas com Domínio T/genética , Temozolomida/farmacologia
3.
Cancer Biother Radiopharm ; 35(3): 214-222, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32196367

RESUMO

Accumulating data showed that cancer stem cells (CSCs) identified by cell surface markers contribute to the initiation, progression, and prognosis of human cancers. In this study, the expression of CSC candidates CD166, CD44, and Lgr5 in 65 cases of esophageal squamous cell carcinoma (ESCC) and 16 cases of control esophageal tissues were examined with immunohistochemistry (IHC). The correlation between tumoral expression levels of these CSC candidates and clinicopathological variables was analyzed. IHC results showed that the expression of CD166 in esophageal control tissues was completely negative, but it was in 87.69% (57/65) ESCC tissues. The expression of CD44 and Lgr5 did not differ between esophageal control tissues and ESCC tissues (p > 0.05). In addition, there were not correlations found among the expression levels of CD166, CD44, and Lgr5 in ESCC tissues. Clinicopathological analysis revealed that the tumoral expression level of CD166 correlated with lymph node involvement and TNM staging in patients with ESCC, and lower tumoral expression of CD44 was found in patients with advanced TNM staging. Kaplan-Meier survival curves suggested that expression level of CD166 appeared to have a negative impact on overall survival rate after surgery in patients with ESCC. Such impact was not found in other two CSC candidates. The authors therefore conclude that CD166 is a potential prognostic biomarker and correlates with advanced progression features in patients with ESCC.


Assuntos
Antígenos CD/biossíntese , Moléculas de Adesão Celular Neuronais/biossíntese , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Proteínas Fetais/biossíntese , Antígenos CD/genética , Moléculas de Adesão Celular Neuronais/genética , Progressão da Doença , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Proteínas Fetais/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
4.
FASEB J ; 34(2): 1970-1982, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31909538

RESUMO

Osterix is a critical transcription factor of mesenchymal stem cell fate, where its loss or loss of Wnt signaling diverts differentiation to a chondrocytic lineage. Intervertebral disc (IVD) degeneration activates the differentiation of prehypertrophic chondrocyte-like cells and inactivates Wnt signaling, but its interactive role with osterix is unclear. First, compared to young-adult (5 mo), mechanical compression of old (18 mo) IVD induced greater IVD degeneration. Aging (5 vs 12 mo) and/or compression reduced the transcription of osterix and notochordal marker T by 40-75%. Compression elevated the transcription of hypertrophic chondrocyte marker MMP13 and pre-osterix transcription factor RUNX2, but less so in 12 mo IVD. Next, using an Ai9/td reporter and immunohistochemical staining, annulus fibrosus and nucleus pulposus cells of young-adult IVD expressed osterix, but aging and compression reduced its expression. Lastly, in vivo LRP5-deficiency in osterix-expressing cells inactivated Wnt signaling in the nucleus pulposus by 95%, degenerated the IVD to levels similar to aging and compression, reduced the biomechanical properties by 45-70%, and reduced the transcription of osterix, notochordal markers and chondrocytic markers by 60-80%. Overall, these data indicate that age-related inactivation of Wnt signaling in osterix-expressing cells may limit regeneration by depleting the progenitors and attenuating the expansion of chondrocyte-like cells.


Assuntos
Envelhecimento/metabolismo , Condrócitos/metabolismo , Condrogênese , Subunidade alfa 1 de Fator de Ligação ao Core/biossíntese , Proteínas Fetais/biossíntese , Degeneração do Disco Intervertebral/metabolismo , Fator de Transcrição Sp7/biossíntese , Proteínas com Domínio T/biossíntese , Envelhecimento/genética , Envelhecimento/patologia , Animais , Antígenos de Diferenciação/biossíntese , Antígenos de Diferenciação/genética , Condrócitos/patologia , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Proteínas Fetais/genética , Regulação da Expressão Gênica , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/patologia , Camundongos , Camundongos Transgênicos , Fator de Transcrição Sp7/genética , Proteínas com Domínio T/genética
5.
Neurosurgery ; 85(3): E527-E542, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30892619

RESUMO

BACKGROUND: Currently, clinical characteristics and prognostic factors of extra-axial chordoma (EAC) remain poorly understood. OBJECTIVE: To characterize clinicopathological characteristics in a large EAC cohort and investigate their correlation with survival. We also attempted to compare these outcomes with axial chordoma (AC). METHODS: Medline and Embase searches (from inception to February 28, 2018) were conducted to identify eligible studies as per predefined criteria. The local database at our center was also retrospectively reviewed to include additional patients. RESULTS: Forty-three studies from the literature and 86 patients from our local institute were identified, resulting in a total of 86 EAC patients and 75 AC patients for analysis. Overall, EAC had similar characteristics to AC, except for having higher CAM5.2 expression, common lobular growth pattern, and better prognosis. Whereas wide surgical resection was consistently associated with favorable survival in both EAC and AC cohorts on univariate analyses, most parameters showed differential prognostic implications between the 2 groups. Significant prognostic factors for local recurrence-free survival on multivariate analysis included type of surgery in both cohorts and tumor Brachyury expression and adjuvant radiotherapy in AC cohort. Multivariate analysis of overall survival demonstrated that type of surgery, tumor Brachyury expression, and duration of symptoms were significant predictors in the AC cohort, whereas none of the analyzed parameters were predictive of overall survival for the EAC group. CONCLUSION: These data suggest potentially distinct biological behaviors between EAC and AC and may provide useful information to better understand the prognostic characteristics and improve the outcome prediction of EAC patients.


Assuntos
Cordoma/diagnóstico por imagem , Cordoma/terapia , Radioterapia Adjuvante/tendências , Fusão Vertebral/tendências , Adulto , Idoso , Cordoma/metabolismo , Feminino , Proteínas Fetais/biossíntese , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Radioterapia Adjuvante/métodos , Estudos Retrospectivos , Fusão Vertebral/métodos , Proteínas com Domínio T/biossíntese
6.
Development ; 145(11)2018 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-29764858

RESUMO

The transcriptional repressor Snail is required for proper differentiation of the tail muscle of ascidian tadpole larvae. Two muscle lineages (B5.1 and B6.4) contribute to the anterior tail muscle cells, and are consecutively separated from a transcriptionally quiescent germ cell lineage at the 16- and 32-cell stages. Concomitantly, cells of these lineages begin to express Tbx6.b (Tbx6-r.b) at the 16- and 32-cell stages, respectively. Meanwhile, Snail expression begins in these two lineages simultaneously at the 32-cell stage. Here, we show that Snail expression is regulated differently between these two lineages. In the B5.1 lineage, Snail was activated through Tbx6.b, which is activated by maternal factors, including Zic-r.a. In the B6.4 lineage, the MAPK pathway was cell-autonomously activated by a constitutively active form of Raf, enabling Zic-r.a to activate Snail independently of Tbx6.b As a result, Snail begins to be expressed at the 32-cell stage simultaneously in these two lineages. Such shortcuts might be required for coordinating developmental programs in embryos in which cells become separated progressively from stem cells, including germline cells.


Assuntos
Ciona intestinalis/embriologia , Desenvolvimento Muscular/genética , Músculos/embriologia , Fatores de Transcrição da Família Snail/genética , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Embrião não Mamífero/metabolismo , Proteínas Fetais/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Larva/crescimento & desenvolvimento , Desenvolvimento Muscular/fisiologia , Músculos/citologia , Proteínas com Domínio T/biossíntese
7.
Andrology ; 6(4): 597-604, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29749711

RESUMO

The T-box transcription factor Brachyury has been considered a cancer-specific marker and a novel oncotarget in solid tumors. Brachyury overexpression has been described in various cancers, being associated with epithelial-mesenchymal transition, metastasis, and poor prognosis. However, its clinical association with testicular germ cell tumor is unknown. We analyzed the expression of Brachyury by immunohistochemistry in a series of well-characterized testicular germ cell tumor samples and at transcript level by in silico analysis. Additionally, we aimed to investigate the clinical significance of Brachyury in testicular germ cell tumor. Brachyury cytoplasm immunostaining was present in 89.6% (86/96) of cases with nuclear staining observed in 24% (23/96) of testicular germ cell tumor. Bioinformatics microarray expression analysis of two independent cohorts of testicular germ cell tumors showed similar results with increased levels of Brachyury in testicular germ cell tumors and metastasis compared with normal testis. Clinically, Brachyury nuclear staining was statistically associated with lower event-free survival (p = 0.04) and overall survival (p = 0.01) in intermediate/high-risk testicular germ cell tumors. Univariate analysis showed that Brachyury nuclear subcellular localization was a predictor of poor prognosis (p = 0.02), while a tendency was observed by multivariate analysis (HR: 3.56, p = 0.06). In conclusion, these results indicate that Brachyury plays an oncogenic role in testicular germ cell tumors and its subcellular localization in the nucleus may constitute a novel biomarker of poor prognosis and a putative oncotarget for intermediate/high-risk testicular germ cell tumor patients.


Assuntos
Biomarcadores Tumorais/análise , Proteínas Fetais/biossíntese , Neoplasias Embrionárias de Células Germinativas/metabolismo , Neoplasias Embrionárias de Células Germinativas/patologia , Proteínas com Domínio T/biossíntese , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patologia , Adolescente , Adulto , Núcleo Celular/metabolismo , Intervalo Livre de Doença , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/mortalidade , Oncogenes , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Testiculares/mortalidade , Adulto Jovem
8.
Br J Cancer ; 118(6): 847-856, 2018 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-29381688

RESUMO

BACKGROUND: Alterations in protein glycosylation have been related to malignant transformation and tumour progression. We recently showed that low mRNA levels of Golgi alpha-mannosidase MAN1A1 correlate with poor prognosis in breast cancer patients. METHODS: We analysed the role of MAN1A1 on a protein level using western blot analysis (n=105) and studied the impact of MAN1A1-related glycosylation on the prognostic relevance of adhesion molecules involved in breast cancer using microarray data (n=194). Functional consequences of mannosidase inhibition using the inhibitor kifunensine or MAN1A1 silencing were investigated in breast cancer cells in vitro. RESULTS: Patients with low/moderate MAN1A1 expression in tumours showed significantly shorter disease-free intervals than those with high MAN1A1 levels (P=0.005). Moreover, low MAN1A1 expression correlated significantly with nodal status, grading and brain metastasis. At an mRNA level, membrane proteins ALCAM and CD24 were only significantly prognostic in tumours with high MAN1A1 expression. In vitro, reduced MAN1A1 expression or mannosidase inhibition led to a significantly increased adhesion of breast cancer cells to endothelial cells. CONCLUSIONS: Our study demonstrates the prognostic role of MAN1A1 in breast cancer by affecting the adhesive properties of tumour cells and the strong influence of this glycosylation enzyme on the prognostic impact of some adhesion proteins.


Assuntos
Neoplasias da Mama/metabolismo , Manosidases/metabolismo , Antígenos CD/biossíntese , Antígenos CD/genética , Antígenos CD/metabolismo , Apoptose/fisiologia , Western Blotting , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Adesão Celular/fisiologia , Moléculas de Adesão Celular Neuronais/biossíntese , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Intervalo Livre de Doença , Feminino , Proteínas Fetais/biossíntese , Proteínas Fetais/genética , Proteínas Fetais/metabolismo , Glicosilação , Humanos , Estimativa de Kaplan-Meier , Manosidases/biossíntese , Manosidases/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Taxa de Sobrevida
9.
Hum Pathol ; 71: 1-7, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28811252

RESUMO

Diffuse malignant mesothelioma of the pleura is a highly aggressive tumor typically associated with short survival. ALCAM (CD166), a type I transmembrane protein, is a member of the immunoglobulin superfamily. In normal cells, ALCAM regulates physiological processes such as angiogenesis and immune response. In cancer, it is associated with neoplastic progression, including invasion, migration, and metastasis. Furthermore, ALCAM is considered one of the cancer stem cell markers such as ALDH1 (ALDH1A1) and SALL4. The PD-L1 (CD274)/PD-1 (PDCD1, CD279) pathway is crucial for the modulation of immune responses in normal cells. Nevertheless, pathologic activation of the PD-L1/PD-1 pathway participates in immune evasion by tumor cells. Many PD-L1-expressing tumor cells have been identified in different types of cancer, including malignant mesothelioma. In this study, 175 well-characterized primary diffuse pleural mesotheliomas, including the epithelioid (n = 148), biphasic (n = 15), and sarcomatoid (n = 12) histotypes, were evaluated immunohistochemically for cancer stem cell markers (ALCAM, ALDH1, and SALL4) and PD-L1 expression. Twenty-five percent of the mesotheliomas (43/175) expressed ALCAM, whereas ALDH1 and SALL4 positivity was seen in 1% to 2% of cases. Thirty-three percent of the analyzed tumors (57/175) contained PD-L1-positive cells. Overall survival was significantly decreased in the cohort of patients with ALCAM- or PD-L1-positive tumors (both P < .01). Furthermore, the multivariate Cox hazards regression analysis identified ALCAM and PD-L1 (both P < 0.01) as potential independent risk factors. Thus, a combination of these 2 markers might be useful for prognostication and planning the treatment of patients with malignant pleural mesothelioma.


Assuntos
Antígenos CD/biossíntese , Antígeno B7-H1/biossíntese , Biomarcadores Tumorais/análise , Moléculas de Adesão Celular Neuronais/biossíntese , Proteínas Fetais/biossíntese , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Neoplasias Pleurais/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Mesotelioma Maligno , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais
10.
Turk Neurosurg ; 28(2): 174-178, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28094431

RESUMO

AIM: Chordomas are rare, slow growing but locally aggressive malignancies of the axial skeleton. Skull base chordomas, due to their intricate anatomical localization, pose significant challenges to managing physicians. In classical and chondroid chordomas, the disease course cannot be reliably determined using only morphological criteria. Brachyury (T Gene) was shown to play a central role in chordoma pathogenesis and several studies also showed that this gene also carries potential as a prognostic biomarker. This study aims to correlate Brachyury expression with the clinical course in surgically treated skull base chordomas. MATERIAL AND METHODS: Chordoma tumor samples from 14 patients with skull base chordomas, diagnosed using histopathological and immunohistochemistry criteria (epithelial membrane antigen (EMA), S100, pan cytokeratin (panCK)) were retrospectively analyzed for Brachyury expression using immunohistochemistry. Brachyury expression was graded using a 4 point semi-quantitative scoring system. Focal (grade II) and diffuse staining (grade III) were considered as overexpression. Patient recurrence-free survival and total survival were compared between Brachyury overexpressing and non-overexpressing groups using Kaplan-Meier survival analysis. RESULTS: Among the stained tumor samples, 85.7% were positive for brachyury expression. In both groups, there was one sample that was negative. We did not observe any significant difference among the groups for staining, grade and percentage of brachyury positive cells. CONCLUSION: Brachyury expression in tumor samples is not a sensitive indicator of prognosis in chordomas.


Assuntos
Biomarcadores Tumorais/análise , Cordoma/patologia , Proteínas Fetais/análise , Neoplasias da Base do Crânio/patologia , Proteínas com Domínio T/análise , Adulto , Cordoma/metabolismo , Feminino , Proteínas Fetais/biossíntese , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias da Base do Crânio/metabolismo , Proteínas com Domínio T/biossíntese
11.
Tumour Biol ; 39(6): 1010428317710575, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28621227

RESUMO

Brachyury has been characterized as a driver of epithelial-mesenchymal transition process which is regarded as an important mechanism of cancer cell invasion and metastatic progression. The status of tumor-infiltrating lymphocytes has been proposed to predict response to neoadjuvant chemotherapy in breast cancer. We investigated the clinical significance and value of tumor-infiltrating lymphocytes and brachyury as biomarkers to predict treatment responses to neoadjuvant chemotherapy in breast cancer. We also examined the correlation of the Neo-Bioscore with tumor-infiltrating lymphocytes and brachyury to indirectly predict long-term outcome. This retrospective study included a series of 44 consecutive patients treated between January 2011 and December 2015. All patient samples were obtained using core needle biopsy before neoadjuvant chemotherapy. The relationship of expression of Brachyury and tumor-infiltrating lymphocyte subsets (CD8+, forkhead box protein 3 tumor-infiltrating lymphocytes) with clinicopathological factors was assessed to identify its predictive role with respect to tumor response to neoadjuvant chemotherapy and the outcome. Of 44 patients, 6 showed no response, 31 had partial response, and 7 demonstrated pathological complete response. Forkhead box protein 3 was significantly higher in the response group than in the no response group (no response = 2.6, partial response = 7.0, complete response = 9.7, p = 0.020). Brachyury expression was inversely associated with response to neoadjuvant chemotherapy, but the difference was not statistically significant ( p = 0.62). We also observed a significant association between forkhead box protein 3 ( p = 0.001) and the Neo-Bioscore, while only a marginal difference was observed with CD8+ expression ( p = 0.074). This study demonstrated that forkhead box protein 3 expression has value as the only independent marker that predicts a good response to neoadjuvant chemotherapy and that it is related with a good prognosis according to the Neo-Bioscore. Brachyury was significantly associated with estrogen receptor positive and human epidermal growth factor receptor 2 negative status; further study would be needed to clarify how it affects treatment prognosis.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Linfócitos T CD8-Positivos/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Proteínas Fetais/biossíntese , Fatores de Transcrição Forkhead/genética , Proteínas com Domínio T/biossíntese , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Proteínas Fetais/genética , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , Receptor ErbB-2/genética , Proteínas com Domínio T/genética , Resultado do Tratamento
12.
Biomed Pharmacother ; 84: 28-33, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27621036

RESUMO

Tamoxifen is effective for treating estrogen receptor-alpha (ERα)-positive breast cancers. However, few molecular mediators of tamoxifen resistance have been elucidated. In the present study, we determine the underlying roles of Brachyury in tamoxifen resistance. Loss- and gain-of-function assay are utilized to confirm the oncogenic roles of Brachyury in breast cancer. Compared with the normal MCF10A cells, Brachyury is commonly overexpressed in breast cancer cell lines. Knockdown of Brachyury inhibits tamoxifen resistance, whereas overexpression of Brachyury enhances tamoxifen resistance as demonstrated increased cell viability and reduced cell apoptosis. Mechanistically, we demonstrate for the first time that Brachyury mediates tamoxifen resistance by regulating Sirtuin-1 (SIRT1). Collectively, our data, as a proof of principle, indicate that Brachyury is a candidate marker for predicting the clinical efficacy of tamoxifen and targeting SIRT1 could overcome resistance to tamoxifen in breast cancer cells.


Assuntos
Biomarcadores Tumorais/biossíntese , Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteínas Fetais/biossíntese , Marcação de Genes/métodos , Sirtuína 1/biossíntese , Proteínas com Domínio T/biossíntese , Tamoxifeno/farmacologia , Biomarcadores Tumorais/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Feminino , Proteínas Fetais/genética , Humanos , Células MCF-7 , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Proteínas com Domínio T/genética
13.
Anticancer Res ; 36(8): 3991-5, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27466504

RESUMO

BACKGROUND/AIM: Activated leukocyte cell adhesion molecule (ALCAM/CD166) as a member of the 'immunoglobulin superfamily' is known to be involved in cancer cell proliferation and migration. The aim of this study was to investigate the expression of ALCAM in neuroblastoma tissues. MATERIALS AND METHODS: ALCAM expression was analyzed in primary neuroblastoma specimens by immunohistochemistry on microarray sections. Histopathological and clinical data were correlated with ALCAM expression and survival analysis was performed. RESULTS: Sixty-six children were included in the study. Strong expression of ALCAM was detected in 52 (79%) of the samples. Weak expression was significantly correlated with the International Neuroblastoma Staging System (INSS) stage (p=0.024) and positive n-MYC amplification (p=0.019). Recurrence-free survival (RFS) and overall survival (OS) were significantly shorter if ALCAM was expressed weakly (p=0.032 and p=0.001). CONCLUSION: Weak ALCAM expression was significantly correlated with established markers for poor prognosis, as well as shorter RFS and OS. ALCAM might be considered as a prognostic marker for infantile neuroblastoma.


Assuntos
Antígenos CD/biossíntese , Biomarcadores Tumorais/biossíntese , Moléculas de Adesão Celular Neuronais/biossíntese , Proteínas Fetais/biossíntese , Neuroblastoma/genética , Prognóstico , Antígenos CD/genética , Biomarcadores Tumorais/genética , Adesão Celular/genética , Moléculas de Adesão Celular Neuronais/genética , Intervalo Livre de Doença , Feminino , Proteínas Fetais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Neuroblastoma/patologia
14.
Sci Rep ; 6: 28995, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27412763

RESUMO

PAIRED (PRD)-like homeobox genes belong to a class of predicted transcription factor genes. Several of these PRD-like homeobox genes have been predicted in silico from genomic sequence but until recently had no evidence of transcript expression. We found recently that nine PRD-like homeobox genes, ARGFX, CPHX1, CPHX2, DPRX, DUXA, DUXB, NOBOX, TPRX1 and TPRX2, were expressed in human preimplantation embryos. In the current study we characterized these PRD-like homeobox genes in depth and studied their functions as transcription factors. We cloned multiple transcript variants from human embryos and showed that the expression of these genes is specific to embryos and pluripotent stem cells. Overexpression of the genes in human embryonic stem cells confirmed their roles as transcription factors as either activators (CPHX1, CPHX2, ARGFX) or repressors (DPRX, DUXA, TPRX2) with distinct targets that could be explained by the amino acid sequence in homeodomain. Some PRD-like homeodomain transcription factors had high concordance of target genes and showed enrichment for both developmentally important gene sets and a 36 bp DNA recognition motif implicated in Embryo Genome Activation (EGA). Our data implicate a role for these previously uncharacterized PRD-like homeodomain proteins in the regulation of human embryo genome activation and preimplantation embryo development.


Assuntos
Blastocisto/metabolismo , Proteínas Fetais/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes Homeobox , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Motivos de Aminoácidos , Sequência de Aminoácidos , Clonagem Molecular , Sequência Consenso , DNA Complementar/genética , Proteínas Fetais/biossíntese , Perfilação da Expressão Gênica , Biblioteca Gênica , Proteínas de Homeodomínio/biossíntese , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Família Multigênica , Especificidade de Órgãos , Células-Tronco Pluripotentes/metabolismo , Regiões Promotoras Genéticas , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Fatores de Transcrição/biossíntese
15.
Expert Rev Mol Diagn ; 16(9): 925-32, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27398729

RESUMO

INTRODUCTION: Many basic studies have provided some evidences for the correlations of CD166 to cancer. However, along with the growing studies on the clinical values of CD166 in cancer areas, some controversial and inconclusive results were obtained. AREAS COVERED: An appropriate query and collection of the published articles was conducted through search in PubMed and EMBASE database. A subsequent systematical and quantitative summary of CD166 related expression and cancer was conducted with meta-analysis to clarify its clinical significance for potential translation as cancer biomarkers. Expert commentary: The overall results suggested total CD166 correlated to cancer risk, membrane CD166 correlated to nodal metastasis and cytoplasmic CD166 correlated to TNM stage, and disease-free survival. The membrane CD166, cytoplasmic CD166 and soluble CD166 showed great potential to be used as a panel of markers for predicting cancer overall survival. We might conclude that CD166 functions as a risk factor for cancers, and the alterations of its different functional isoforms were observed to correlate with specific or interplayed clinical outcomes.


Assuntos
Antígenos CD/biossíntese , Biomarcadores Tumorais/biossíntese , Moléculas de Adesão Celular Neuronais/biossíntese , Proteínas Fetais/biossíntese , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Neoplasias/metabolismo , Intervalo Livre de Doença , Humanos , Neoplasias/mortalidade , Fatores de Risco , Taxa de Sobrevida
16.
Cancer Res ; 76(17): 5151-62, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27328731

RESUMO

miR-214 and miR-148b have been proposed to antagonize the effects of each other in enabling or blocking metastasis, respectively. In this study, we provide evidence deepening their role and interrelationship in the process of metastatic dissemination. Depleting miR-214 or elevating miR-148b blocked the dissemination of melanoma or breast cancer cells, an effect that could be accentuated by dual alteration. Mechanistic investigations indicated that dual alteration suppressed passage of malignant cells through the blood vessel endothelium by reducing expression of the cell adhesion molecules ITGA5 and ALCAM. Notably, transendothelial migration in vitro and extravasation in vivo impaired by singly alternating miR-214 or miR-148b could be overridden by overexpression of ITGA5 or ALCAM in the same tumor cells. In clinical specimens of primary breast cancer or metastatic melanoma, we found a positive correlation between miR-214 and ITGA5 or ALCAM along with an inverse correlation of miR-214 and miR-148b in the same specimens. Our findings define an antagonistic relationship of miR-214 and miR-148b in determining the dissemination of cancer cells via tumor-endothelial cell interactions, with possible implications for microRNA-mediated therapeutic interventions aimed at blocking cancer extravasation. Cancer Res; 76(17); 5151-62. ©2016 AACR.


Assuntos
Neoplasias da Mama/patologia , Melanoma/patologia , MicroRNAs/genética , Invasividade Neoplásica/genética , Animais , Antígenos CD/biossíntese , Neoplasias da Mama/genética , Moléculas de Adesão Celular/biossíntese , Moléculas de Adesão Celular Neuronais/biossíntese , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Células Endoteliais/patologia , Feminino , Proteínas Fetais/biossíntese , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Immunoblotting , Melanoma/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
17.
PLoS One ; 11(2): e0150236, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26919721

RESUMO

BACKGROUND: Long non-coding RNAs (lncRNAs) are a class of RNA molecules with diverse regulatory functions during embryonic development, normal life, and disease in higher organisms. However, research on the role of lncRNAs in cardiovascular diseases and in particular heart failure is still in its infancy. The exceptionally well conserved nuclear lncRNA Metastasis associated in lung adenocarcinoma transcript 1 (Malat-1) is a regulator of mRNA splicing and highly expressed in the heart. Malat-1 modulates hypoxia-induced vessel growth, activates ERK/MAPK signaling, and scavenges the anti-hypertrophic microRNA-133. We therefore hypothesized that Malat-1 may act as regulator of cardiac hypertrophy and failure during cardiac pressure overload induced by thoracic aortic constriction (TAC) in mice. RESULTS: Absence of Malat-1 did not affect cardiac hypertrophy upon pressure overload: Heart weight to tibia length ratio significantly increased in WT mice (sham: 5.78±0.55, TAC 9.79±1.82 g/mm; p<0.001) but to a similar extend also in Malat-1 knockout (KO) mice (sham: 6.21±1.12, TAC 8.91±1.74 g/mm; p<0.01) with no significant difference between genotypes. As expected, TAC significantly reduced left ventricular fractional shortening in WT (sham: 38.81±6.53%, TAC: 23.14±11.99%; p<0.01) but to a comparable degree also in KO mice (sham: 37.01±4.19%, TAC: 25.98±9.75%; p<0.05). Histological hallmarks of myocardial remodeling, such as cardiomyocyte hypertrophy, increased interstitial fibrosis, reduced capillary density, and immune cell infiltration, did not differ significantly between WT and KO mice after TAC. In line, the absence of Malat-1 did not significantly affect angiotensin II-induced cardiac hypertrophy, dysfunction, and overall remodeling. Above that, pressure overload by TAC significantly induced mRNA levels of the hypertrophy marker genes Nppa, Nppb and Acta1, to a similar extend in both genotypes. Alternative splicing of Ndrg2 after TAC was apparent in WT (isoform ratio; sham: 2.97±0.26, TAC 1.57±0.40; p<0.0001) and KO mice (sham: 3.64±0.37; TAC: 2.24±0.76; p<0.0001) and interestingly differed between genotypes both at baseline and after pressure overload (p<0.05 each). CONCLUSION: These findings confirm a role for the lncRNA Malat-1 in mRNA splicing. However, no critical role for Malat-1 was found in pressure overload-induced heart failure in mice, despite its reported role in vascularization, ERK/MAPK signaling, and regulation of miR-133.


Assuntos
Cardiomegalia/genética , Insuficiência Cardíaca/genética , Splicing de RNA/genética , RNA Longo não Codificante/fisiologia , Remodelação Ventricular/genética , Proteínas Adaptadoras de Transdução de Sinal , Angiotensina II/metabolismo , Angiotensina II/toxicidade , Animais , Aorta Torácica , Cardiomegalia/etiologia , Constrição Patológica/complicações , Cruzamentos Genéticos , Proteínas Fetais/biossíntese , Proteínas Fetais/genética , Regulação da Expressão Gênica/genética , Insuficiência Cardíaca/etiologia , Heterozigoto , Ligadura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Pressão , Proteínas/genética , Proteínas/metabolismo , RNA Longo não Codificante/genética
18.
Circulation ; 133(11): 1081-92, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26841808

RESUMO

BACKGROUND: Adult mammalian cardiomyocytes (CMs) have the potential to proliferate, but this is not sufficient to generate adequate CMs after myocardial infarction (MI). The transcription factor Tbx20 is required for CM proliferation during development and adult CM homeostasis. The ability of Tbx20 overexpression (Tbx20(OE)) to promote adult CM proliferation and to improve cardiac function after MI was examined. METHODS AND RESULTS: Tbx20(OE) was induced specifically in adult mouse differentiated CMs. Increased CM proliferation and fetal-like characteristics were found in Tbx20(OE) hearts compared with controls without causing pathology 4 weeks after Tbx20(OE) at baseline. Moreover, Tbx20(OE) in adult CM after MI significantly improved survival, cardiac function, and infarct size 4 weeks after MI. Improved cardiac repair, as indicated by increased CM proliferation and capillary density, was observed in the MI border zone of Tbx20(OE) hearts compared with controls. Expression of proliferation activator (cyclin D1, E1, and IGF1) and fetal contractile protein (ssTNI, ßMHC) mRNA was increased whereas negative cell-cycle regulators (p21, Meis1) were decreased in Tbx20(OE) hearts compared with controls under both baseline and MI conditions. Tbx20(OE) in adult hearts activates multiple proproliferation pathways, including Akt, YAP and BMP. Interestingly, p21, Meis1, and a novel cell-cycle inhibitory gene, Btg2, are directly bound and repressed by Tbx20 with induction of proliferation in neonatal CM. CONCLUSIONS: Tbx20(OE), specifically in adult CM, activates multiple cardiac proliferative pathways, directly represses cell-cycle inhibitory genes p21, Meis1, and Btg2, promotes adult CM proliferation; and preserves cardiac performance after MI.


Assuntos
Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas com Domínio T/fisiologia , Animais , Proteínas de Ciclo Celular/biossíntese , Proteínas de Ciclo Celular/genética , Divisão Celular , Tamanho Celular/efeitos dos fármacos , Eletrocardiografia , Feminino , Proteínas Fetais/biossíntese , Proteínas Fetais/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Genes cdc/efeitos dos fármacos , Coração/fisiopatologia , Proteínas Imediatamente Precoces/biossíntese , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/fisiologia , Camundongos , Camundongos Transgênicos , Proteínas Musculares/biossíntese , Proteínas Musculares/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Miócitos Cardíacos/patologia , Tamanho do Órgão/efeitos dos fármacos , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Método Simples-Cego , Proteínas com Domínio T/biossíntese , Proteínas com Domínio T/genética , Tamoxifeno/farmacologia , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/fisiologia
19.
Gene Expr Patterns ; 19(1-2): 52-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26272686

RESUMO

Formins are highly conserved heterogeneous family of proteins with several isoforms having significant contribution in multiple cellular functions. Formins play crucial role in remodelling of actin cytoskeleton and thus play important role in cell motility. Formins are also involved in many cellular activities like determining cell polarity, cytokinesis and morphogenesis. Formins are multi domain protein with characteristic homodimeric formin homology 2 (FH2) domain. It nucleates the actin filaments and its activity is regulated by the presence of characteristic formin homology 1 (FH1) domain. In higher mammals like human and mouse fifteen different formin isoforms are present. However the function and expression pattern of each and every formin in different adult tissues are not well characterized. Here we have found that multiple formins are expressing in each adult tissue of mouse, irrespective of their origin from the germ layer. Formins are also expressing from early stage of development to the adulthood in brain. The expression of many formins in a single tissue of adult mouse indicates that regulation of actin cytoskeleton dynamics by formins may be crucial for physiological processes like wound healing, tissue repairing, exocytosis, endocytosis, synapse formation and maintenance. Expression of FMNL2 and Fhdc1 are high in adult mouse brain as compare to embryonic stages. Higher expression of FMNL2 and Fhdc1 indicates that FMNL2 and Fhdc1 might be very important for the adult brain functions.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Proteínas dos Microfilamentos/biossíntese , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Fatores Etários , Animais , Proteínas Fetais/biossíntese , Forminas , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso , Proteínas Nucleares/biossíntese , Especificidade de Órgãos , Isoformas de Proteínas , Estrutura Terciária de Proteína
20.
J Neurosurg ; 123(4): 1036-41, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26162041

RESUMO

OBJECT: Although chondrosarcomas rarely arise in the skull base, chondrosarcomas and chordomas are the 2 major malignant bone neoplasms occurring at this location. The distinction of these 2 tumors is important, but this distinction is occasionally problematic because of radiological and histological overlap. Unlike chordoma and extracranial chondrosarcoma, no case series presenting a whole-genome analysis of skull base chondrosarcomas (SBCSs) has been reported. The goal of this study is to clarify the genetic characteristics of SBCSs and contrast them with those of chordomas. METHODS: The authors analyzed 7 SBCS specimens for chromosomal copy number alterations (CNAs) using comparative genomic hybridization (CGH). They also examined IDH1 and IDH2 mutations and brachyury expression. RESULTS: In CGH analyses, the authors detected CNAs in 6 of the 7 cases, including chromosomal gains of 8q21.1, 19, 2q22-q32, 5qcen-q14, 8q21-q22, and 15qcen-q14. Mutation of IDH1 was found with a high frequency (5 of 7 cases, 71.4%), of which R132S was most frequently mutated. No IDH2 mutations were found, and immunohistochemical staining for brachyury was negative in all cases. CONCLUSIONS: To the best of the authors' knowledge, this is the first whole-genome study of an SBSC case series. Their findings suggest that these tumors are molecularly consistent with a subset of conventional central chondrosarcomas and different from skull base chordomas.


Assuntos
Condrossarcoma/genética , Hibridização Genômica Comparativa , Neoplasias da Base do Crânio/genética , Adulto , Idoso , Condrossarcoma/metabolismo , Feminino , Proteínas Fetais/biossíntese , Humanos , Isocitrato Desidrogenase/genética , Pessoa de Meia-Idade , Mutação , Neoplasias da Base do Crânio/metabolismo , Proteínas com Domínio T/biossíntese , Adulto Jovem
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