Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 59
Filtrar
Mais filtros

Base de dados
Tipo de documento
País de afiliação
Intervalo de ano de publicação
1.
J Cell Physiol ; 234(6): 9297-9307, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30317661

RESUMO

In recent years, osteosarcoma survival rates have failed to improve significantly with conventional treatment modalities because of the development of chemotherapeutic resistance. The human breast cancer resistance protein/ATP binding cassette subfamily G member 2 (BCRP/ABCG2), a member of the ATP-binding cassette family, uses ATP hydrolysis to expel xenobiotics and chemotherapeutics from cells. CCN family member 2 (CCN2) is a secreted protein that modulates the biological function of cancer cells, enhanced ABCG2 protein expression and activation in this study via the α6ß1 integrin receptor and increased osteosarcoma cell viability. CCN2 treatment downregulated miR-519d expression, which promoted ABCG2 expression. In a mouse xenograft model, knockdown of CCN2 expression increased the therapeutic effect of doxorubicin, which was reversed by ABCG2 overexpression. Our data show that CCN2 increases ABCG2 expression and promotes drug resistance through the α6ß1 integrin receptor, whereas CCN2 downregulates miR-519d. CCN2 inhibition may represent a new therapeutic concept in osteosarcoma.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Osteossarcoma/genética , Animais , Sequência de Bases , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Humanos , Integrina alfa6beta1/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Biológicos , Transdução de Sinais
2.
Cell Physiol Biochem ; 51(1): 337-355, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30453282

RESUMO

BACKGROUND/AIMS: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy is a clinical option for non-small cell lung cancer (NSCLC) harboring activating EGFR mutations or for cancer with wild-type (WT) EGFR when chemotherapy has failed. MET receptor activation or MET gene amplification was reported to be a major mechanism of acquired resistance to EGFR-TKI therapy in NSCLC cells. Leukocyte cell-derived chemotaxin 2 (LECT2) is a multifunctional cytokine that was shown to suppress metastasis of hepatocellular carcinoma via inhibiting MET activity. Until now, the biological function responsible for LECT2's action in human NSCLC remains unclear. METHODS: LECT2-knockout (KO) mice and NOD/SCID/IL2rgnull (NSG) mice were respectively used to investigate the effects of LECT2 on the tumorigenicity and metastasis of murine (Lewis lung carcinoma, LLC) and human (HCC827) lung cancer cells. The effect of LECT2 on in vitro cell proliferation was evaluated, using MTS and colony formation assays. The effect of LECT2 on cell motility was evaluated using transwell migration and invasion assays. An enzyme-linked immunosorbent assay was performed to detect secreted LECT2 in plasma and media. Co-immunoprecipitation and Western blot assays were used to investigate the underlying mechanisms of LECT2 in NSCLC cells. RESULTS: Compared to WT mice, mice with LECT2 deletion exhibited enhanced growth and metastasis of LLC cells, and survival times decreased in LLC-implanted mice. Overexpression of LECT2 in orthotopic human HCC827 xenografts in NSG mice resulted in significant inhibition of tumor growth and metastasis. In vitro, overexpression of LECT2 or treatment with a recombinant LECT2 protein impaired the colony-forming ability and motility of NSCLC cells (HCC827 and PC9) harboring high levels of activated EGFR and MET. Mechanistic investigations found that LECT2 bound to MET and EGFR to antagonize their activation and further suppress their common downstream pathways: phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase. CONCLUSION: EGFR-MET signaling is critical for aggressive behaviors of NSCLC and is recognized as a therapeutic target for NSCLC especially for patients with acquired resistance to EGFR-TKI therapy. Our findings demonstrate, for the first time, that LECT2 functions as a suppressor of the progression of NSCLC by targeting EGFR-MET signaling.


Assuntos
Receptores ErbB/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Metástase Neoplásica , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Blood ; 128(12): 1578-89, 2016 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-27338098

RESUMO

Epstein-Barr virus (EBV), an oncogenic human virus, is associated with several lymphoproliferative disorders, including Burkitt lymphoma, Hodgkin disease, diffuse large B-cell lymphoma (DLBCL), and posttransplant lymphoproliferative disorder (PTLD). In vitro, EBV transforms primary B cells into lymphoblastoid cell lines (LCLs). Recently, several studies have shown that receptor tyrosine kinases (RTKs) play important roles in EBV-associated neoplasia. However, details of the involvement of RTKs in EBV-regulated B-cell neoplasia and malignancies remain largely unclear. Here, we found that erythropoietin-producing hepatocellular receptor A4 (EphA4), which belongs to the largest RTK Eph family, was downregulated in primary B cells post-EBV infection at the transcriptional and translational levels. Overexpression and knockdown experiments confirmed that EBV-encoded latent membrane protein 1 (LMP1) was responsible for this EphA4 suppression. Mechanistically, LMP1 triggered the extracellular signal-regulated kinase (ERK) pathway and promoted Sp1 to suppress EphA4 promoter activity. Functionally, overexpression of EphA4 prevented LCLs from proliferation. Pathologically, the expression of EphA4 was detected in EBV(-) tonsils but not in EBV(+) PTLD. In addition, an inverse correlation of EphA4 expression and EBV presence was verified by immunochemical staining of EBV(+) and EBV(-) DLBCL, suggesting EBV infection was associated with reduced EphA4 expression. Analysis of a public data set showed that lower EphA4 expression was correlated with a poor survival rate of DLBCL patients. Our findings provide a novel mechanism by which EphA4 can be regulated by an oncogenic LMP1 protein and explore its possible function in B cells. The results provide new insights into the role of EphA4 in EBV(+) PTLD and DLBCL.


Assuntos
Infecções por Vírus Epstein-Barr/complicações , Linfoma Difuso de Grandes Células B/mortalidade , Transtornos Linfoproliferativos/mortalidade , Receptor EphA4/metabolismo , Proteínas da Matriz Viral/metabolismo , Células Cultivadas , Regulação para Baixo , Infecções por Vírus Epstein-Barr/virologia , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Herpesvirus Humano 4 , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/virologia , Transtornos Linfoproliferativos/metabolismo , Transtornos Linfoproliferativos/virologia , Prognóstico , Receptor EphA4/genética , Transdução de Sinais , Taxa de Sobrevida , Proteínas da Matriz Viral/genética
4.
Ann Surg Oncol ; 24(13): 4033-4041, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28744792

RESUMO

BACKGROUND: Human 3ß-hydroxysteroid dehydrogenase type 1 (HSD3B1) plays a vital role in steroidogenesis in breast tumors and may therefore be a suitable target for treatment of breast cancer. This study investigated the role of HSD3B1 in the pathogenesis of breast cancer in clinical and experimental settings. METHODS: Expression of HSD3B1 in primary tumors of 258 breast cancer patients was evaluated by immunohistochemistry. Screening of breast cancer cell lines indicated that triple-negative MDA-MB-231 cells expressed HSD3B1. The effects from genetic and pharmacologic inhibition of HSD3B1 were assessed in vitro and in vivo. RESULTS: The findings showed that 44% of the 258 breast cancers were HSD3B1-positive. The HSD3B1-positivity was associated with advanced-stage disease (p = 0.009) and reduced recurrence-free survival (p = 0.048) but not with tumor subtype or estrogen receptor status. Silencing of HSD3B1 or treatment with an HSD3B1 inhibitor (trilostane) reduced colony formation in breast cancer cells. Knockdown of HSD3B1 inhibited cell proliferation and migration. Analysis of a murine xenograft tumor model indicated that trilostane significantly slowed tumor growth. CONCLUSIONS: Expression of HSD3B1 in breast cancer is negatively associated with prognosis. The study found HSD3B1 to be a potential therapeutic target for breast cancer independent of estrogen receptor status.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Complexos Multienzimáticos/metabolismo , Progesterona Redutase/metabolismo , Receptores de Estrogênio/metabolismo , Esteroide Isomerases/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/metabolismo , Ciclo Celular , Movimento Celular , Proliferação de Células , Di-Hidrotestosterona/análogos & derivados , Di-Hidrotestosterona/farmacologia , Feminino , Seguimentos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Complexos Multienzimáticos/antagonistas & inibidores , Complexos Multienzimáticos/genética , Progesterona Redutase/antagonistas & inibidores , Progesterona Redutase/genética , Prognóstico , RNA Interferente Pequeno/genética , Esteroide Isomerases/antagonistas & inibidores , Esteroide Isomerases/genética , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Environ Toxicol ; 32(2): 434-444, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26872304

RESUMO

Apigenin (4',5,7-trihydroxyflavone), a flavonoid commonly found in fruits and vegetables, has anticancer properties in various malignant cancer cells. However, the molecular basis of the anticancer effect remains to be elucidated. In this study, we investigated the cellular mechanisms underlying the induction of cell cycle arrest by apigenin. Our results showed that apigenin at the nonapoptotic induction concentration inhibited cell proliferation and induced cell cycle arrest at the G2/M phase in the MDA-MB-231 breast cancer cell line. Immunoblot analysis indicated that apigenin suppressed the expression of cyclin A, cyclin B, and cyclin-dependent kinase-1 (CDK1), which control the G2-to-M phase transition in the cell cycle. In addition, apigenin upregulated p21WAF1/CIP1 and increased the interaction of p21WAF1/CIP1 with proliferating cell nuclear antigen (PCNA), which inhibits cell cycle progression. Furthermore, apigenin significantly inhibited histone deacetylase (HDAC) activity and induced histone H3 acetylation. The subsequent chromatin immunoprecipitation (ChIP) assay indicated that apigenin increased acetylation of histone H3 in the p21WAF1/CIP1 promoter region, resulting in the increase of p21WAF1/CIP1 transcription. In a tumor xenograft model, apigenin effectively delayed tumor growth. In these apigenin-treated tumors, we also observed reductions in the levels of cyclin A and cyclin B and increases in the levels of p21WAF1/CIP1 and acetylated histone H3. These findings demonstrate for the first time that apigenin can be used in breast cancer prevention and treatment through epigenetic regulation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 434-444, 2017.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apigenina/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fase G2/efeitos dos fármacos , Histonas/metabolismo , Acetilação , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/análise , Histona Desacetilases/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Biochim Biophys Acta ; 1843(2): 387-97, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24184161

RESUMO

High-level expression of vascular endothelial growth factor (VEGF)-C is associated with chemoresistance and adverse prognosis in acute myeloid leukemia (AML). Our previous study has found that VEGF-C induces cyclooxygenase-2 (COX-2) expression in AML cell lines and significant correlation of VEGF-C and COX-2 in bone marrow specimens. COX-2 has been reported to mediate the proliferation and drug resistance in several solid tumors. Herein, we demonstrated that the VEGF-C-induced proliferation of AML cells is effectively abolished by the depletion or inhibition of COX-2. The expression of endothelin-1 (ET-1) rapidly increased following treatment with VEGF-C. We found that ET-1 was also involved in the VEGF-C-mediated proliferation of AML cells, and that recombinant ET-1 induced COX-2 mRNA and protein expressions in AML cells. Treatment with the endothelin receptor A (ETRA) antagonist, BQ 123, or ET-1 shRNAs inhibited VEGF-C-induced COX-2 expression. Flow cytometry and immunoblotting revealed that VEGF-C induces S phase accumulation through the inhibition of p27 and the upregulation of cyclin E and cyclin-dependent kinase-2 expressions. The cell-cycle-related effects of VEGF-C were reversed by the depletion of COX-2 or ET-1. The depletion of COX-2 or ET-1 also suppressed VEGF-C-induced increases in the bcl-2/bax ratio and chemoresistance against etoposide and cytosine arabinoside in AML cells. We also demonstrated VEGF-C/ET-1/COX-2 axis-mediated chemoresistance in an AML xenograft mouse model. Our findings suggest that VEGF-C induces COX-2-mediated resistance to chemotherapy through the induction of ET-1 expression. Acting as a key regulator in the VEGF-C/COX-2 axis, ET-1 represents a potential target for ameliorating resistance to chemotherapy in AML patients.


Assuntos
Ciclo-Oxigenase 2/biossíntese , Resistencia a Medicamentos Antineoplásicos , Endotelina-1/metabolismo , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Fator C de Crescimento do Endotélio Vascular/metabolismo , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Humanos , Masculino , Camundongos , Regulação para Cima/efeitos dos fármacos , Fator C de Crescimento do Endotélio Vascular/farmacologia
7.
Hepatology ; 59(3): 974-85, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24114941

RESUMO

UNLABELLED: Leukocyte cell-derived chemotoxin 2 (LECT2) has been shown to act as a tumor suppressor in hepatocellular carcinoma (HCC). However, the underlying mechanism has not yet been completely defined. Here, we employ a LECT2-affinity column plus liquid chromatography coupled with tandem mass spectrometry to identify LECT2-binding proteins and found that MET receptor strongly interacted with LECT2 protein. Despite the presence of hepatocyte growth factor, the LECT2 binding causes an antagonistic effect to MET receptor activation through recruitment of protein tyrosine phosphatase 1B. The antagonistic effect of LECT2 on MET activation also mainly contributes to the blockage of vascular invasion and metastasis of HCC. Furthermore, serial deletions and mutations of LECT2 showed that the HxGxD motif is primarily responsible for MET receptor binding and its antagonistic effects. CONCLUSION: These findings reveal a novel, specific inhibitory function of LECT2 in HCC by the direct binding and inactivation of MET, opening a potential avenue for treating MET-related liver cancer.


Assuntos
Carcinoma Hepatocelular/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Hepáticas/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Carcinoma Hepatocelular/metabolismo , Células Hep G2 , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Neoplasias Hepáticas/metabolismo , Invasividade Neoplásica/patologia , Fosforilação/fisiologia , Ligação Proteica/fisiologia , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-met/química
8.
J Cutan Pathol ; 42(9): 639-44, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25924981

RESUMO

CD20-positive natural killer (NK)/T-cell lymphoma is extremely rare. We describe a case of a CD20-positive nodal NK/T-cell lymphoma with cutaneous involvement in a 32-year-old man. The patient presented with fever, night sweats, right inguinal lymphadenopathy and multiple violaceous to erythematous nodules and plaques on the back and bilateral legs. Immunohistochemical analysis showed diffusely and strongly positive staining for CD3, CD3 epsilon, CD43, CD56, TIA-1 and CD20 but negative staining for other B-cell markers, including CD79a and PAX-5 and T-cell markers CD5 and CD7. The tumor cell nuclei were diffusely positive for Epstein-Barr virus-encoded RNA in situ hybridization. A partial clinical response was observed after chemotherapy, indicated by the decreased size of the lymph nodes and skin lesions. It is a diagnostic challenge to deal with lymphoma cells that present with the surface proteins of both T- and B-cells.


Assuntos
Antígenos CD20/metabolismo , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Células T Matadoras Naturais/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Adulto , Linfócitos B/patologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Humanos , Linfonodos/patologia , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/virologia , Masculino , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/virologia
9.
Am J Dermatopathol ; 37(6): 462-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25747812

RESUMO

The bowenoid transformation of seborrheic keratosis (SK) has rarely been reported. The purpose of this study is to identify their diagnostic immunohistochemical features and association with human papillomavirus (HPV) infection. Skin biopsy specimens of the phenomenon were retrieved from 2001 to 2010. Benign SK, Bowen disease, bowenoid papulosis, and squamous cell carcinoma were included as controls. All specimens were stained for hematoxylin and eosin, Ki-67, p21, p16, p53, and cyclin D1. Polymerase chain reaction-amplified HPV DNA was analyzed. Seventeen cases of SK with bowenoid transformation were identified. The immunohistochemical pattern of bowenoid transformation was similar to that of Bowen disease and bowenoid papulosis. The malignant cells exhibited increased expressions of p16, p21, and ki-67 and a decreased expression of cyclin D1 (P < 0.01). HPV DNA was detected in 5 cases of bowenoid transformation. In conclusion, a portion of the cases of SK with bowenoid transformation were associated with HPV infection. Selective immunohistochemical stains were helpful in the diagnosis of malignant change in these cases.


Assuntos
Biomarcadores Tumorais/análise , Doença de Bowen/patologia , Ceratose Seborreica/patologia , Neoplasias Cutâneas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Bowen/virologia , Transformação Celular Neoplásica/patologia , Feminino , Humanos , Imuno-Histoquímica , Ceratose Seborreica/virologia , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/complicações , Neoplasias Cutâneas/virologia
10.
Mol Cancer ; 13: 189, 2014 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-25115793

RESUMO

BACKGROUND: Ovarian cancer (OCa) peritoneal metastasis is the leading cause of cancer-related deaths in women with limited therapeutic options available for treating it and poor prognosis, as the underlying mechanism is not fully understood. METHOD: The clinicopathological correlation of G9a expression was assessed in tumor specimens of ovarian cancer patients. Knockdown or overexpression of G9a in ovarian cancer cell lines was analysed with regard to its effect on adhesion, migration, invasion and anoikis-resistance. In vivo biological functions of G9a were tested by i.p. xenograft ovarian cancer models. Microarray and quantitative RT-PCR were used to analyze G9a-regulated downstream target genes. RESULTS: We found that the expression of histone methyltransferase G9a was highly correlated with late stage, high grade, and serous-type OCa. Higher G9a expression predicted a shorter survival in ovarian cancer patients. Furthermore, G9a expression was higher in metastatic lesions compared with their corresponding ovarian primary tumors. Knockdown of G9a expression suppressed prometastatic cellular activities including adhesion, migration, invasion and anoikis-resistance of ovarian cancer cell lines, while G9a over-expression promoted these cellular properties. G9a depletion significantly attenuated the development of ascites and tumor nodules in a peritoneal dissemination model. Importantly, microarray and quantitative RT-PCR analysis revealed that G9a regulates a cohort of tumor suppressor genes including CDH1, DUSP5, SPRY4, and PPP1R15A in ovarian cancer. Expression of these genes was also inversely correlated with G9a expression in OCa specimens. CONCLUSION: We propose that G9a contributes to multiple steps of ovarian cancer metastasis and represents a novel target to combat this deadly disease.


Assuntos
Biomarcadores Tumorais/metabolismo , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Animais , Anoikis , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Análise Multivariada , Invasividade Neoplásica , Neoplasias Ovarianas/genética , Neoplasias Peritoneais/genética , Prognóstico , Transdução de Sinais/genética
11.
Am J Pathol ; 182(2): 363-74, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23219426

RESUMO

Histopathological classification of human prostate cancer (PCA) relies on the morphological assessment of tissue specimens but has limited prognostic value. To address this deficiency, we performed comparative transcriptome analysis of human prostatic acini generated in a three-dimensional basement membrane that recapitulates the differentiated morphological characteristics and gene expression profile of a human prostate glandular epithelial tissue. We then applied an acinar morphogenesis-specific gene profile to two independent cohorts of patients with PCA (total n = 79) and found that those with tumors expressing this profile, which we designated acini-like tumors, had a significantly lower risk of postoperative relapse compared with those tumors with a lower correlation (hazard ratio, 0.078; log-rank test P = 0.009). Multivariate analyses showed superior prognostic prediction performance using this classification system compared with clinical criteria and Gleason scores. We prioritized the genes in this profile and identified programmed cell death protein 4 (PDCD4) and Kruppel-like factor 6 (KLF6) as critical regulators and surrogate markers of prostatic tissue architectures, which form a gene signature that robustly predicts clinical prognosis with a remarkable accuracy in several large series of PCA tumors (total n = 161; concordance index, 0.913 to 0.951). Thus, by exploiting the genomic program associated with prostate glandular differentiation, we identified acini-like PCA and related molecular markers that significantly enhance prognostic prediction of human PCA.


Assuntos
Células Acinares/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Perfilação da Expressão Gênica , Fatores de Transcrição Kruppel-Like/metabolismo , Morfogênese/genética , Próstata/patologia , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Células Acinares/metabolismo , Idoso , Proteínas Reguladoras de Apoptose/genética , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Fator 6 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos/genética , Prognóstico , Próstata/crescimento & desenvolvimento , Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/cirurgia , Proteínas Proto-Oncogênicas/genética , Proteínas de Ligação a RNA/genética , Recidiva
12.
Int J Mol Sci ; 14(3): 5264-83, 2013 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-23466879

RESUMO

Prostate cancer is the fifth most common cancer overall in the world. Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, most prostate cancer patients receiving the androgen ablation therapy ultimately develop recurrent castration-resistant tumors within 1-3 years after treatment. The median overall survival time is 1-2 years after tumor relapse. Chemotherapy shows little effect on prolonging survival for patients with metastatic hormone-refractory prostate cancer. More than 80% of prostate tumors acquire mutation or deletion of tumor suppressor phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/Akt signaling, indicating that inhibition of PI3K/Akt might be a potential therapy for advanced prostate tumors. Caffeic acid phenethyl ester (CAPE) is a strong antioxidant extracted from honeybee hive propolis. CAPE is a well-known NF-κB inhibitor. CAPE has been used in folk medicine as a potent anti-inflammatory agent. Recent studies indicate that CAPE treatment suppresses tumor growth and Akt signaling in human prostate cancer cells. We discuss the potential of using CAPE as a treatment for patients with advanced prostate cancer targeting Akt signaling pathway in this review article.

13.
Toxicol Appl Pharmacol ; 261(1): 105-15, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22503731

RESUMO

The induction of matrix metalloproteinase (MMP)-9 is particularly important for the invasiveness of various cancer cells. Osthole, a natural coumarin derivative extracted from traditional Chinese medicines, is known to inhibit the proliferation of a variety of tumor cells, but the effect of osthole on the invasiveness of tumor cells is largely unknown. This study determines whether and by what mechanism osthole inhibits invasion in CL1-5 human lung adenocarcinoma cells. Herein, we found that osthole effectively inhibited the migratory and invasive abilities of CL1-5 cells. A zymographic assay showed that osthole inhibited the proteolytic activity of MMP-9 in CL1-5 cells. Inhibition of migration, invasion, and MMP2 and/or MMP-9 proteolytic activities was also observed in other lung adenocarcinoma cell lines (H1299 and A549). We further found that osthole inhibited MMP-9 expression at the messenger RNA and protein levels. Moreover, a chromatin immunoprecipitation assay showed that osthole inhibited the transcriptional activity of MMP-9 by suppressing the DNA binding activity of nuclear factor (NF)-κB in the MMP-9 promoter. Using reporter assays with point-mutated promoter constructs further confirmed that the inhibitory effect of osthole requires an NF-κB binding site on the MMP-9 promoter. Western blot and immunofluorescence assays demonstrated that osthole inhibited NF-κB activity by inhibiting IκB-α degradation and NF-κB p65 nuclear translocation. In conclusion, we demonstrated that osthole inhibits NF-κB-mediated MMP-9 expression, resulting in suppression of lung cancer cell invasion and migration, and osthole might be a potential agent for preventing the invasion and metastasis of lung cancer.


Assuntos
Adenocarcinoma/tratamento farmacológico , Cumarínicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Metaloproteinase 9 da Matriz/genética , Adenocarcinoma/patologia , Sítios de Ligação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Imunofluorescência , Humanos , Neoplasias Pulmonares/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Medicina Tradicional Chinesa , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Invasividade Neoplásica , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo
14.
J Pediatr Endocrinol Metab ; 24(9-10): 783-6, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22145476

RESUMO

Poorly differentiated thyroid carcinoma (PDTC) is a rare disease with a poor prognosis in children. We describe a 9-year-old boy with a thyroid nodule composed of cystic and solid components, which became completely solid and hypoechoic and was subsequently proved to be PDTC. The tumor consisted of small- to intermediate-size round cells in a trabecular or insular pattern with hyperchromatic nuclei and mitotic figures. The tumor cells were positive for thyroid transcription factor 1 and thyroglobulin. PDTC is morphologically and prognostically between the well-differentiated and anaplastic carcinomas. It must be distinguished from the solid variant of papillary carcinoma and well-differentiated follicular carcinoma with a predominantly solid/trabecular growth pattern. The tumor stage was T2N0M0. The patient was treated with total thyroidectomy, left-sided neck level VI lymph node dissection, recombinant human thyrotropin-stimulated 131I ablation therapy, and thyroid-stimulating hormone suppression. Malignancy should be suspected in a cystic thyroid nodule that becomes solid and hypoechoic.


Assuntos
Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/patologia , Diferenciação Celular , Criança , Terapia Combinada/métodos , Humanos , Radioisótopos do Iodo/uso terapêutico , Masculino , Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/terapia , Nódulo da Glândula Tireoide/cirurgia , Nódulo da Glândula Tireoide/terapia , Tireoidectomia , Tireotropina/antagonistas & inibidores
15.
Int J Cancer ; 127(3): 555-67, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19957335

RESUMO

Oncogenic activation of the Wnt signaling pathway is common in cancers, but mutation of beta-catenin in ovarian cancer is rare. In addition to genetic events, epigenetic modification of secreted frizzled-related protein (SFRP) family has been shown to be important in regulating Wnt signaling. Although high degree of homology is observed in the same family, different SFRPs may have opposing effects on the same process. We reported recently that a Wnt antagonist, SFRP5, is downregulated frequently through promoter hypermethylation and that this hypermethylation is associated with overall survival in ovarian cancer. The aim of this study was to analyze the function of SFRP5 in ovarian cancer. Functional assays including measuring cell proliferation, invasion, colony formation and xenograft were performed using ovarian cancer cell lines with overexpression of SFRP5 or a short hairpin RNA silencing. The methylation status of SFRP5 in relation to cisplatin resistance in ovarian cancer patients was analyzed. Restoration of the expression of SFRP5 attenuated Wnt signaling in ovarian cancer cells and suppressed cancer cell growth, invasion of cells and tumorigenicity in mice. These effects were independent of the canonical pathway. The expression of SFRP5 inhibited epithelial-mesenchymal transition (EMT). The restoration of SFRP5 downregulated AKT2 and sensitized ovarian cancer cells to chemotherapy. These effects are consistent with the poor response to platinum-based chemotherapy in patients with methylation of SFRP5. Our data suggested that epigenetic silencing of SFRP5 leads to oncogenic activation of the Wnt pathway and contributes to ovarian cancer progression and chemoresistance through the TWIST-mediated EMT and AKT2 signaling.


Assuntos
Epigênese Genética , Proteínas do Olho/genética , Inativação Gênica , Proteínas de Membrana/genética , Neoplasias Ovarianas/genética , Transdução de Sinais , Proteínas Wnt/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Antineoplásicos/farmacologia , Sequência de Bases , Western Blotting , Cisplatino/farmacologia , Metilação de DNA , Primers do DNA , Resistencia a Medicamentos Antineoplásicos , Feminino , Imunofluorescência , Humanos , Neoplasias Ovarianas/metabolismo , Fenótipo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
Int J Gynecol Pathol ; 29(3): 239-42, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20407322

RESUMO

A 39-year-old female presented with abdominal distension. A right adnexal mass was found on physical examination, which was shown to be cystic on ultrasound. An exploratory laparotomy revealed a right ovarian mass, which was removed and a staging procedure was performed. Histologically, the mass was a borderline ovarian tumor with stromal microinvasion and hemangiomatous mural nodules.


Assuntos
Adenocarcinoma Mucinoso/patologia , Cistadenocarcinoma Mucinoso/patologia , Hemangioma/patologia , Neoplasias Ovarianas/patologia , Adenocarcinoma Mucinoso/cirurgia , Adulto , Cistadenocarcinoma Mucinoso/cirurgia , Feminino , Hemangioma/cirurgia , Histocitoquímica , Humanos , Neoplasias Ovarianas/cirurgia
17.
Lab Chip ; 20(2): 424-433, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31872843

RESUMO

Agglutination is an antigen-antibody reaction with visible expression of aggregation of the antigens and their corresponding antibodies. Applications extend to the identification of acute bacterial infection, hemagglutination, such as blood grouping, and diagnostic immunology. Our finger-powered agglutination lab chip with external CMOS image sensing was developed to support a platform for inexpensive, rapid point-of-care (POC) testing applications related to agglutination effects. In this paper, blood grouping (ABO and Rh grouping) was utilized to demonstrate the function of our finger-powered agglutination lab chip with CMOS image sensing. Blood antibodies were preloaded into the antibody reaction chamber in the lab chip. The blood sample was pushed through the antibody reaction chamber using finger-powered pressure actuation to initiate a hemagglutination reaction to identify the blood type at the on-chip detection area using our homemade CMOS image sensing mini-system. Finger-powered actuation without the need for external electrical pumping is excellent for low-cost POC applications, but the pumping liquid volume per finger push is hard to control. In our finger-powered agglutination lab chip with CMOS image sensing, we minimized the effects of different finger push depths and achieved robust performance for the test results with different push depths. The driving sample volume per finger push is about 0.79 mm3. For different chips and different pushes, the driven sample volume per finger push was observed to vary in the range of 0.64 to 1.18 mm3. The red blood cells were separated from the plasma on-chip after the whole blood sample was finger pumped and before the red blood cells reached the antibody chamber via an embedded plasma-separation membrane. Our homemade CMOS image mini-system robustly read and identified the agglutination results on our agglutination lab chip.


Assuntos
Anticorpos/imunologia , Antígenos/imunologia , Eritrócitos/imunologia , Dispositivos Lab-On-A-Chip , Imagem Óptica , Testes Imediatos , Aglutinação , Reações Antígeno-Anticorpo , Eritrócitos/citologia , Humanos
18.
Eur J Med Chem ; 191: 112118, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32113126

RESUMO

Highly expressed in cancer 1 (Hec1) plays an essential role in mitosis and is correlated with cancer formation, progression, and survival. Phosphorylation of Hec1 by Nek2 kinase is essential for its mitotic function, thus any disruption of Hec1/Nek2 protein-protein interaction has potential for cancer therapy. We have developed T-1101 tosylate (9j tosylate, 9j formerly known as TAI-95), optimized from 4-aryl-N-pyridinylcarbonyl-2-aminothiazole of scaffold 9 by introducing various C-4' substituents to enhance potency and water solubility, as a first-in-class oral clinical candidate for Hec1 inhibition with potential for cancer therapy. T-1101 has good oral absorption, along with potent in vitro antiproliferative activity (IC50: 14.8-21.5 nM). It can achieve high concentrations in Huh-7 and MDA-MB-231 tumor tissues, and showed promise in antitumor activity in mice bearing human tumor xenografts of liver cancer (Huh-7), as well as of breast cancer (BT474, MDA-MB-231, and MCF7) with oral administration. Oral co-administration of T-1101 halved the dose of sorafenib (25 mg/kg to 12.5 mg/kg) required to exhibit comparable in vivo activity towards Huh-7 xenografts. Cellular events resulting from Hec1/Nek2 inhibition with T-1101 treatment include Nek2 degradation, chromosomal misalignment, and apoptotic cell death. A combination of T-1101 with either of doxorubicin, paclitaxel, and topotecan in select cancer cells also resulted in synergistic effects. Inactivity of T-1101 on non-cancerous cells, a panel of kinases, and hERG demonstrates cancer specificity, target specificity, and cardiac safety, respectively. Subsequent salt screening showed that T-1101 tosylate has good oral AUC (62.5 µM·h), bioavailability (F = 77.4%), and thermal stability. T-1101 tosylate is currently in phase I clinical trials as an orally administered drug for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Proteínas do Citoesqueleto/antagonistas & inibidores , Descoberta de Drogas , Quinases Relacionadas a NIMA/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas do Citoesqueleto/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células K562 , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos SCID , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinases Relacionadas a NIMA/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Distribuição Tecidual
19.
Clin Drug Investig ; 29(1): 65-71, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19067476

RESUMO

Unresectable hepatocellular carcinoma (HCC) has a poor therapeutic outcome. We report here on a 40-year-old male HCC patient who had undergone partial hepatectomy and was refractory to therapeutic embolization. In addition, the tumour expressed phosphorylated extracellular signal-regulated kinase and CD34. Sorafenib was administered as salvage treatment and resulted in a rapid decline in alpha-fetoprotein (AFP) levels. However, this was accompanied by a grade 3 skin reaction, which improved as sorafenib dosage was gradually reduced. Unfortunately, reducing the dose of sorafenib also resulted in a rebound in AFP levels and portal vein thrombosis was noted thereafter. Sorafenib 800 mg/day was resumed, but the tumour failed to respond. Intensity-modulated radiation therapy (IMRT) combined with sorafenib was administered, resulting in marked tumour shrinkage and causing recurrence of the systemic skin reaction and development of photosensitivity. The patient survived for 20 months after the start of sorafenib treatment. This case suggests that the combination of sorafenib and IMRT might provide clinical benefits in patients with HCC who express potential targets but fail to respond to sorafenib; however, skin reactions should be monitored.


Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Piridinas/uso terapêutico , Adulto , Antineoplásicos/efeitos adversos , Benzenossulfonatos/efeitos adversos , Humanos , Masculino , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/efeitos adversos , Radioterapia de Intensidade Modulada/instrumentação , Radioterapia de Intensidade Modulada/métodos , Terapia de Salvação , Sorafenibe , Resultado do Tratamento
20.
Mol Diagn Ther ; 23(5): 645-656, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31347028

RESUMO

BACKGROUND: Colorectal cancer (CRC) is among the most frequently occurring cancers worldwide and its incidence is forecasted to increase. Testing for KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations in colorectal tissue biopsy samples has become a crucial tool to guide therapeutic decisions for personalized treatment. OBJECTIVE: The objective of this study was to determine the diagnostic sensitivity and specificity of the IntelliPlex™ KRAS G12/13 Mutation Kit using clinical specimens compared to Sanger sequencing as the reference method. METHODS: A total of 248 formalin-fixed paraffin-embedded (FFPE) tissue samples, with CRC tumors comprising more than 10% of the whole tissue sample, were included in the study and analyzed for specific KRAS mutations in codons 12 and 13. For samples with discordant results between Sanger sequencing and the IntelliPlex™ KRAS G12/13 Mutation Kit, Pyrosequencing was utilized to resolve the KRAS mutational status. RESULTS: Sequencing determined 153 specimens as KRAS wild-type genotype while the IntelliPlex™ KRAS G12/13 Mutation Kit confirmed 139 of the wild-type cases, resulting in a clinical specificity of 90.8% (95% confidence interval (CI) 85.12-94.91). All 95 specimens with a reported mutation in codons 12 or 13 of KRAS by sequencing were also reported as non-wild-type by the IntelliPlex™ KRAS G12/13 Mutation Kit, resulting in a clinical sensitivity to detect KRAS mutations of 100% (95% CI 96.19-100). CONCLUSIONS: The IntelliPlex™ KRAS G12/13 Mutation Kit demonstrates suitable specificity and sensitivity for use in clinical laboratories to determine the mutational status of KRAS codons 12 and 13.


Assuntos
Códon , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Análise Mutacional de DNA , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Kit de Reagentes para Diagnóstico , Neoplasias Colorretais/terapia , Análise Mutacional de DNA/métodos , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Sensibilidade e Especificidade , Análise de Sequência de DNA
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA