RESUMO
Integrin α6 (ITGA6) forms integrin receptors with either integrin ß1 (ITGB1) or integrin ß4 (ITGB4). How it functions to regulate hepatocellular carcinoma (HCC) progression is not well-elucidated. We found that ITGA6 RNA and protein expression levels are significantly elevated in human HCC tissues in comparison with paired adjacent nontumor tissues by RNA sequencing, RT-qPCR, Western blotting and immunofluorescence staining. Stable knockdown of ITGA6 with different ITGA6 shRNA expression lentivectors significantly inhibited proliferation, migration and anchorage-independent growth of HCC cell lines in vitro, and xenograft tumor growth in vivo. The inhibition of anchorage-dependent and -independent growth of HCC cell lines was also confirmed with anti-ITGA6 antibody. ITGA6 knockdown was shown to induce cell-cycle arrest at G0/G1 phase. Immunoprecipitation assay revealed apparent interaction of ITGA6 with ITGB4, but not ITGB1. Expression studies showed that ITGA6 positively regulates the expression of ITGB4 with no or negative regulation of ITGB1 expression. Finally, while high levels of ITGA6 and ITGB4 together were associated with significantly worse survival of HCC patients in TCGA data set, the association was not significant for high levels of ITGA6 and ITGB1. In conclusion, ITGA6 is upregulated in HCC tumors and has a malignant promoting role in HCC cells through integrin α6ß4 complex. Thus, integrin α6ß4 may be a therapeutic target for treating patients with HCC.
Assuntos
Carcinoma Hepatocelular , Integrina alfa6 , Integrina alfa6beta4 , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Integrina alfa6/genética , Integrina alfa6/metabolismo , Integrina alfa6beta4/genética , Integrina alfa6beta4/metabolismo , Integrina beta4/genética , Integrina beta4/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologiaRESUMO
Gliomaassociated oncogene family zinc finger 2 (Gli2), a key component of the hedgehog signaling pathway, has been previously demonstrated to promote the malignant properties of prostate cancer in vitro. However, the role of Gli2 in the development of castrationresistant prostate cancer (CRPC) has yet to be fully elucidated. In the present study, Gli2 expression was knocked down in androgenresponsive prostate cancer cells using an inducible Gli2 short hairpin RNA. Suppression of Gli2 expression resulted in significant reduction of cell viability, increased the proportion of cells in the G0/G1 phases of the cell cycle and reduced the expression of genes associated with cell cycle progression. Gli2 knockdown sensitized both androgendependent and independent prostate cancer cells to the antiandrogen drug Casodex and prevented the outgrowth of LNCaP prostate cancer cells. In addition, Gli2 knockdown significantly suppressed the development of CRPC in a LNCaP xenograft mouse model, which was reversed by the reexpression of Gli2. In conclusion, to the best of our knowledge, the present study was the first occasion in which the essential role of Gli2 in the development of CRPC was demonstrated, providing a potential therapeutic target for the intervention of CRPC.
Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Proteínas Nucleares/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Proteína Gli2 com Dedos de Zinco/metabolismo , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Anilidas/farmacologia , Anilidas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , RNA Interferente Pequeno/metabolismo , Compostos de Tosil/farmacologia , Compostos de Tosil/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína Gli2 com Dedos de Zinco/antagonistas & inibidores , Proteína Gli2 com Dedos de Zinco/genéticaRESUMO
Deregulation of apoptosis is central to cancer progression and a major obstacle to effective treatment. The Bcl-2 gene family members play important roles in the regulation of apoptosis and are frequently altered in cancers. One such member is pro-apoptotic protein Bcl-2-related Ovarian Killer (BOK). Despite its critical role in apoptosis, the regulation of BOK expression is poorly understood in cancers. Here, we discovered that miR-296-5p regulates BOK expression by binding to its 3'-UTR in breast cancers. Interestingly, miR-296-5p also regulates the expression of anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1), which is highly expressed in breast cancers. Our results reveal that Mcl-1 and BOK constitute a regulatory feedback loop as ectopic BOK expression induces Mcl-1, whereas silencing of Mcl-1 results in reduced BOK levels in breast cancer cells. In addition, we show that silencing of Mcl-1 but not BOK reduced the long-term growth of breast cancer cells. Silencing of both Mcl-1 and BOK rescued the effect of Mcl-1 silencing on breast cancer cell growth, suggesting that BOK is important for attenuating cell growth in the absence of Mcl-1. Depletion of BOK suppressed caspase-3 activation in the presence of paclitaxel and in turn protected cells from paclitaxel-induced apoptosis. Furthermore, we demonstrate that glycogen synthase kinase (GSK3) α/ß interacts with BOK and regulates its level post-translationally in breast cancer cells. Taken together, our results suggest that fine tuning of the levels of pro-apoptotic protein BOK and anti-apoptotic protein Mcl-1 may decide the fate of cancer cells to either undergo apoptosis or proliferation.
RESUMO
BACKGROUND: Left heart mechanical circulatory support (MCS) through the left chest via the pulmonary vein and descending thoracic aorta is a good option for patients with an inaccessible anterior mediastinum and/or poor peripheral access. MATERIALS AND METHODS: We report the case of a 19-year-old small female with a newly discovered bulky primary mediastinal diffuse large B-cell lymphoma (PMBL) who developed refractory inverted Takotsubo cardiomyopathy (TC) with cardiogenic shock. RESULTS: Temporary MCS was implemented in order to stabilize the patient and proceed with a chemotherapy treatment. Given the patient's oncologic "frozen" mediastinum and the presence of poor peripheral arterial access, the left heart temporary MCS was successfully implanted through a left mini-thoracotomy via the left inferior pulmonary vein and descending thoracic aorta. CONCLUSIONS: This is the first report of temporary MCS to treat inverted TC and diffuse PMBL.
Assuntos
Derivação Cardíaca Esquerda , Linfoma Difuso de Grandes Células B/complicações , Neoplasias do Mediastino/complicações , Cardiomiopatia de Takotsubo/cirurgia , Feminino , Derivação Cardíaca Esquerda/métodos , Humanos , Cardiomiopatia de Takotsubo/etiologia , Toracotomia , Adulto JovemRESUMO
Las pacientes mayores de 35 años son las que se encuentran en mayor riesgo de exéresis quirúrgica de los ovarios por diferentes causas y la mayor ocurrencia se da en la CNS, de las cuales una mayoría son procedentes del área urbana y rural que han llegado hasta nivel básico en el HMIGU, en relación a la CNS, y en menor porcentaje a nivel técnico y universitario.El tipo de cirugía realizado en mayor porcentaje es la salpingooferectomía bilateral (SOB) retiro de ambos ovarios incluída las trompas, acompañado de la administración de la TRH que es más frecuente en la CNS, por el seguimiento más controlado que se realiza a éstas pacientes y por el nivel de educación de las mismas. Es así que las pacientes que presentan síntomas de supresión hormonal no consideran estos como normales, sino prevenibles y curables, no así las pacientes que no han obtenido suficiente orientación respecto a las consultas sobre la importancia del tratamiento con la TRH
Assuntos
Seguimentos , OvariectomiaRESUMO
Las pacientes mayores de 35 años son las que se encuentran en mayor riesgo de exéresis quirúrgica de los ovarios por diferentes causas y la mayor ocurrencia se da en la CNS, de las cuales una mayoría son procedentes del área urbana y rural que han llegado hasta nivel básico en el HMIGU, en relación a la CNS, y en menor porcentaje a nivel técnico y universitario.El tipo de cirugía realizado en mayor porcentaje es la salpingooferectomía bilateral (SOB) retiro de ambos ovarios incluída las trompas, acompañado de la administración de la TRH que es más frecuente en la CNS, por el seguimiento más controlado que se realiza a éstas pacientes y por el nivel de educación de las mismas. Es así que las pacientes que presentan síntomas de supresión hormonal no consideran estos como normales, sino prevenibles y curables, no así las pacientes que no han obtenido suficiente orientación respecto a las consultas sobre la importancia del tratamiento con la TRH
Assuntos
Seguimentos , OvariectomiaRESUMO
De acuerdo a estos datos se concluyò que los niveles de plomo en sangre se relacionan con el conocimiento de los trabajadores de los diferentes talleres acerca de los riesgos del plomo, encontradose elevados en aquellos que no tenian conocimiento, las actitudes frente al conocimiento de los riesgos del plomo es optimo debido a que los trabajadores que conocen acerca de los riesgos son los que emplean mas barreras de protección en relación a aquellos que no...
