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1.
Rinsho Shinkeigaku ; 59(7): 442-447, 2019 Jul 31.
Artigo em Japonês | MEDLINE | ID: mdl-31243254

RESUMO

A 69-year-old man presented with a history of personality change for several years. He was admitted to our hospital due to partial seizure. A cerebrospinal fluid test and an electroencephalogram showed no specific abnormalities, but brain magnetic resonance imaging revealed abnormal findings in the right temporal pole, bilateral amygdala to hippocampus, and insular cortex. He was diagnosed with limbic encephalitis accompanied by partial seizure, and received infusion of an antiepileptic agent and acyclovir. Additional examinations for malignancy and autoimmune disease were performed, and neck CT and MRI revealed a neck tumor. Neck lymph node biopsy suggested lymph node metastasis of a neuroendocrine neoplasm derived from other organs. He did not want aggressive treatment involving surgical resection and chemotherapy, and thus, conservative treatment was chosen by an otorhinolaryngologist and immunotherapy was not used. After discharge, the neck tumor grew gradually. To manage the focal mass effect, chemotherapy and surgical resection followed by chemoradiotherapy were performed by the otorhinolaryngologist on days 244 and 325 of the disease course, respectively. Histology of resected tissues disclosed neck neuroendocrine carcinoma derived from a submandibular gland. His personality change improved temporarily after surgical resection, but then worsened again with regrowth of the tumor. He died on day 723. After death, a blood test revealed the presence of anti-amphiphysin antibody. This case suggests that neck neuroendocrine carcinoma can induce paraneoplastic limbic encephalitis, and in such cases, early surgical resection of the neck tumor with suspected lymph node metastasis is necessary both to control symptoms associated with encephalitis and to exclude carcinoma derived from the neck itself.


Assuntos
Carcinoma Neuroendócrino/complicações , Encefalite Límbica/etiologia , Neoplasias da Glândula Submandibular/complicações , Idoso , Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Carcinoma Neuroendócrino/diagnóstico , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/terapia , Terapia Combinada , Evolução Fatal , Humanos , Metástase Linfática , Proteínas do Tecido Nervoso/imunologia , Neoplasias da Glândula Submandibular/diagnóstico , Neoplasias da Glândula Submandibular/patologia , Neoplasias da Glândula Submandibular/terapia
2.
Am J Cancer Res ; 7(4): 881-891, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28469960

RESUMO

Hypopharyngeal carcinoma is one of the worst prognostic malignancies among head and neck carcinomas. Therefore, a good biomarker should be identified to predict the best therapeutic option before starting the treatment. In cell models, p62/SQSTM1 levels affected the Nrf2-Keap1 pathway, ROS levels, GSH/GSSG ratios and cell growth, especially under irradiation rather than under CDDP exposure, which was toxic despite p62/SQSTM1 status. In a clinical cohort of hypopharyngeal carcinomas, high levels of p62/SQSTM1 significantly predicted poor prognosis (log-rank test, Chi-square value = 6.750, P = 0.0094) and maximum critical risk (Cox proportional hazard ratio = 4.405, P = 0.0086), especially in the radiotherapy group. Therefore, when p62/SQSTM1 is elevated in the biopsy section, hypopharyngeal carcinoma should be treated with surgical and/or chemotherapeutic options.

3.
Head Neck ; 34(5): 674-80, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21717524

RESUMO

UNLABELLED: 7 BACKGROUND: No generally agreed-upon method is available for predicting the prognosis of salivary gland cancers. RB1-inducible coiled-coil 1 (RB1CC1) is a positive regulator for the retinoblastoma tumor suppressor (RB1) pathway, and is a suitable marker for evaluating the clinical course of breast cancer. We investigated whether RB1CC1 predicts the prognosis of salivary gland cancers. METHODS: Molecules involved in the RB1CC1 pathway, including RB1CC1, RB1, p53, and Ki-67, were evaluated immunohistochemically in 36 cases of salivary gland cancers. The relationships between clinicopathologic features and disease-free-survival intervals were analyzed by a Kaplan-Meier log-rank test and a multivariate Cox proportional hazard regression. RESULTS: Nuclear RB1CC1 loss in the tumors was significantly associated with a worse disease-free survival (log-rank test, chi-square value = 11.644, p = .0006), and was the maximum critical risk (multivariate Cox proportional hazard ratio = 11.112, 95% confidence interval [CI] = 1.776-69.510, p = .0100). CONCLUSIONS: Nuclear expression of RB1CC1 predicts a better clinical outcome and is useful in the follow-up of salivary gland cancers.


Assuntos
Proteínas Tirosina Quinases/metabolismo , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Relacionadas à Autofagia , Biomarcadores Tumorais/metabolismo , Carcinoma/metabolismo , Carcinoma/mortalidade , Carcinoma/terapia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias das Glândulas Salivares/terapia , Adulto Jovem
4.
Oncol Rep ; 26(4): 805-12, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21637919

RESUMO

RB1-inducible coiled-coil 1 (RB1CC1, also known as FIP200) is involved in dephosphorylation and increase of retinoblastoma tumor suppressor protein (RB1), but the RB1CC1 molecular mechanism in the dephosphorylation of RB1 is not fully understood. We determined that RB1CC1 activates the expression of p16 (also called INK4a/CDKN2a) through the activation of its promoter, using chromatin immunoprecipitation (ChIP) and p16 promoter-luciferase reporter assays. In addition, RB1CC1 essentially requires binding with hSNF5 (also known as BAF47/INI1, a chromatin-remodeling factor) to activate the p16 promoter, in order to enhance the RB1 pathway and acts as a tumor suppressor. Evaluation of the RB1CC1 mechanism of action is expected to provide useful information for clinical practice and future therapeutic strategies in human cancers.


Assuntos
Neoplasias da Mama/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Genes p16 , Proteínas Tirosina Quinases/genética , Fatores de Transcrição/genética , Proteínas Relacionadas à Autofagia , Neoplasias da Mama/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células HeLa , Humanos , Imuno-Histoquímica , Regiões Promotoras Genéticas , Proteínas Tirosina Quinases/metabolismo , Proteína do Retinoblastoma/biossíntese , Proteína SMARCB1 , Fatores de Transcrição/metabolismo , Ativação Transcricional , Transfecção
5.
Cancer Res ; 71(13): 4598-607, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21571861

RESUMO

RECQL1 and WRN proteins are RecQ DNA helicases that participate in suppression of DNA hyper-recombination and repair. In this study, we report evidence supporting their candidacy as cancer therapeutic targets. In hypopharyngeal carcinomas, which have the worst prognosis among head and neck squamous cell carcinomas (HNSCC) that are rapidly rising in incidence, we found that RECQL1 and WRN proteins are highly expressed and that siRNA-mediated silencing of either gene suppressed carcinoma cell growth in vitro. Similarly, siRNA administration in a murine xenograft model of hypopharyngeal carcinoma markedly inhibited tumor growth. Moreover, combining either siRNA with cis-platinum (II) diammine dichloride significantly augmented the in vivo anticancer effects of this drug that is used commonly in HNSCC treatment. Notably, we observed no recurrence of some tumors following siRNA treatment in this model. Our findings offer a preclinical proof of concept for RECQL1 and WRN proteins as novel therapeutic targets to treat aggressive HNSCC and perhaps other cancers.


Assuntos
Carcinoma/enzimologia , Carcinoma/terapia , Exodesoxirribonucleases/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias Hipofaríngeas/enzimologia , Neoplasias Hipofaríngeas/terapia , Terapia de Alvo Molecular/métodos , Neoplasias de Células Escamosas/enzimologia , Neoplasias de Células Escamosas/terapia , RecQ Helicases/antagonistas & inibidores , Animais , Carcinoma/tratamento farmacológico , Carcinoma/genética , Carcinoma de Células Escamosas , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Terapia Combinada , Exodesoxirribonucleases/biossíntese , Exodesoxirribonucleases/genética , Inativação Gênica , Células HeLa , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Neoplasias Hipofaríngeas/tratamento farmacológico , Neoplasias Hipofaríngeas/genética , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias de Células Escamosas/tratamento farmacológico , Neoplasias de Células Escamosas/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Distribuição Aleatória , RecQ Helicases/biossíntese , RecQ Helicases/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , Helicase da Síndrome de Werner , Ensaios Antitumorais Modelo de Xenoenxerto
6.
PLoS One ; 5(6): e11404, 2010 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-20614030

RESUMO

RB1-inducible coiled-coil 1 (RB1CC1, also known as FIP200) plays a role in the enhancement of the RB1 pathway through the direct binding to a GC-rich region 201bp upstream (from the initiation ATG) of the RB1 promoter. Here, we identified hSNF5 and p53 as the binding partners of RB1CC1 by immunoprecipitation and immunofluorescence assays. Interaction between these molecules and the RB1 pathway was analyzed by the assays of chromatin immunoprecipitation, luciferase-reporter, reverse transcription-polymerase chain reaction and immunoblot. The tumor growth suppression by RB1CC1 was evaluated by flow cytometry or by a cell growth assay. The nuclear RB1CC1 complex involving hSNF5 and/or p53 activated transcription of RB1, p16 and p21, and suppressed tumor cell growth. Furthermore, nuclear RB1CC1 expression significantly correlated with those of RB1 and p16 in breast cancer tissue in vivo, and the Ki-67 proliferation index was dependent on p53 as well as RB1CC1. The present study indicates that RB1CC1 together with hSNF5 and/or p53 enhances the RB1 pathway through transcriptional activation of RB1, p16 and p21. Evaluation of RB1CC1 expression combined with RB1 and p53 status is expected to provide useful information in clinical practice and future therapeutic strategies in breast cancer.


Assuntos
Proliferação de Células , Neoplasias/patologia , Proteínas Tirosina Quinases/fisiologia , Proteína do Retinoblastoma/metabolismo , Proteínas Relacionadas à Autofagia , Imunoprecipitação da Cromatina , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Eletroforese em Gel de Poliacrilamida , Humanos , Neoplasias/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Proteína do Retinoblastoma/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína SMARCB1 , Espectrometria de Massas em Tandem , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo
7.
PLoS One ; 5(12): e15737, 2010 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-21203526

RESUMO

RB1-inducible coiled-coil 1 (RB1CC1) plays a significant role in the enhancement of the retinoblastoma tumor suppressor (RB1) pathway and is involved in breast cancer development. However, RB1CC1's role in clinical progression of breast cancer has not yet been evaluated, so, as a first step, it is necessary to establish its usefulness as a tool to evaluate breast cancer patients. In this report, we have analyzed the correlation between abnormalities in the RB1CC1 pathway and long-term prognosis, because disease-specific death in later periods (>5 years) of the disease is a serious problem in breast cancer. Breast cancer tissues from a large cohort in Japan were evaluated by conventional immunohistochemical methods for the presence of the molecules involved in the RB1CC1 pathway, including RB1CC1, RB1, p53, and other well-known prognostic markers for breast cancer, such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The correlation between the immunohistochemical results and clinical outcomes of 323 breast cancer patients was analyzed using a Kaplan-Meier log-rank test and a multivariate Cox proportional hazards regression analysis. Absence of nuclear RB1CC1 expression was associated with the worst prognosis (Log-rank test, Chi-Square value = 17.462, p<0.0001). Dysfunction of either one of RB1CC1, RB1, or p53 was associated with the highest risk for cancer-specific death, especially related to survival lasting more than 5 years (multivariate Cox proportional hazard ratio = 3.951, 95% Confidence Interval =1.566-9.967, p = 0.0036). Our present data demonstrate that the combined evaluation of RB1CC1, RB1 and p53 by conventional immunohistochemical analysis provides an accurate prediction of the long-term prognoses of breast cancer patients, which can be carried out as a routine clinical examination.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Tirosina Quinases/biossíntese , Proteínas Tirosina Quinases/genética , Proteína do Retinoblastoma/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Relacionadas à Autofagia , Neoplasias da Mama/epidemiologia , Núcleo Celular/metabolismo , Estudos de Coortes , Feminino , Humanos , Imuno-Histoquímica/métodos , Japão , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais
8.
Int J Cancer ; 125(4): 861-7, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19437535

RESUMO

RB1-inducible coiled-coil 1 (RB1CC1, also known as FIP200) is a tumor suppressor implicated in the regulation of RB1 (retinoblastoma 1) expression. However, the molecular mechanism of RB1 regulation by RB1CC1 has not been elucidated. Here, we demonstrate that nuclear RB1CC1 binds to the RB1 promoter using chromatin immunoprecipitation assays with anti-RB1CC1 antibody. Luciferase assays with RB1 promoter reporter plasmids revealed that RB1CC1 activated the RB1 promoter through the 201 bp upstream GC-rich region (from the initiation ATG). Electrophoretic mobility shift assay and Western blot analysis supported RB1CC1 binding to the GC-rich region of the RB1 promoter. In addition, the C-terminus of RB1CC1 was required for nuclear localization and subsequent RB1 promoter activation. Furthermore, the expression levels of RB1CC1 and RB1 significantly correlated with in vivo breast cancer tissues as determined by immunohistochemical analysis. These data indicate that nuclear RB1CC1 directly activates the RB1 promoter to enhance RB1 expression in cancer cells. Evaluation of RB1CC1 in various types of human cancer tissues is expected to provide useful information for clinical practice and future therapeutic strategies.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Regiões Promotoras Genéticas/genética , Proteínas Tirosina Quinases/metabolismo , Proteína do Retinoblastoma/genética , Proteínas Relacionadas à Autofagia , Western Blotting , Neoplasias da Mama/patologia , Núcleo Celular/metabolismo , Imunoprecipitação da Cromatina , Citoplasma/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Sequência Rica em GC , Humanos , Técnicas Imunoenzimáticas , Luciferases/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção , Células Tumorais Cultivadas
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