RESUMEN
MicroRNAs (miRNAs) are important epigenetic regulators of gene expression. Although several miRNAs have been implicated in osteosarcoma, their role in regulation of osteosarcoma cancer stem cells (CSCs) remains unknown. Here we demonstrated that miR-26a is downregulated in osteosarcoma CSCs when derived by either sarcosphere generation, chemodrug or aldehyde dehydrogenase (ALDH) activity selection. Lentiviral overexpression of miR-26a in ZOS and 143B osteosarcoma cells decreases the expression of stem cell markers and suppresses sarcosphere formation, as well as ALDH activity. Moreover, miR-26a overexpression inhibits the tumor cell growth both in vitro and in vivo. We further demonstrate that miR-26a directly target Jagged1, one of the Notch ligand, and that its tumor suppressive effects are mediated through inhibition of Jagged1/Notch signaling. Importantly, reduced miR-26a expression, as determined by in situ hybridization in patient tumors (n=92), is associated with lung metastasis and poor overall survival of osteosarcoma patients. Together, these data suggest the essential role of miR-26a/Jagged1/Notch pathway in regulating the stem cell-like traits of osteosarcoma cells and provide a potential target for osteosarcoma therapy.
Asunto(s)
Neoplasias Óseas/patología , Proteína Jagged-1/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , MicroARNs/genética , Osteosarcoma/patología , Regiones no Traducidas 3' , Adolescente , Adulto , Animales , Neoplasias Óseas/genética , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Masculino , Ratones , Trasplante de Neoplasias , Células Madre Neoplásicas/metabolismo , Osteosarcoma/genética , Pronóstico , Transducción de Señal , Análisis de Supervivencia , Adulto JovenRESUMEN
Steroid receptor co-activator-3 (SRC-3/AIB1) is an oncogene that is amplified and overexpressed in many human cancers. However, the molecular mechanisms that regulate 'activated SRC-3 oncoprotein' turnover during tumorigenesis remain to be elucidated. Here, we report that speckle-type POZ protein (SPOP), a cullin 3 (CUL3)-based ubiquitin ligase, is responsible for SRC-3 ubiquitination and proteolysis. SPOP interacts directly with an SRC-3 phospho-degron in a phosphorylation-dependent manner. Casein kinase IÉ phosphorylates the S102 in this degron and promotes SPOP-dependent turnover of SRC-3. Short hairpin RNA knockdown and overexpression experiments substantiated that the SPOP/CUL3/Rbx1 ubiquitin ligase complex promotes SRC-3 turnover. A systematic analysis of the SPOP genomic locus revealed that a high percentage of genomic loss or loss of heterozygosity occurs at this locus in breast cancers. Furthermore, we demonstrate that restoration of SPOP expression inhibited SRC-3-mediated oncogenic signaling and tumorigenesis, thus positioning SPOP as a tumor suppressor.
Asunto(s)
Proteínas Cullin/metabolismo , Proteínas Nucleares/metabolismo , Coactivador 3 de Receptor Nuclear/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proteínas Portadoras/metabolismo , Caseína Cinasa 1 épsilon/metabolismo , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Desnudos , Proteínas Nucleares/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , ARN Interferente Pequeño/metabolismo , Proteínas Represoras/genéticaRESUMEN
We demonstrated short segments of a superconducting wire that meets or exceeds performance requirements for many large-scale applications of high-temperature superconducting materials, especially those requiring a high supercurrent and/or a high engineering critical current density in applied magnetic fields. The performance requirements for these varied applications were met in 3-micrometer-thick YBa2Cu3O(7-delta) films epitaxially grown via pulsed laser ablation on rolling assisted biaxially textured substrates. Enhancements of the critical current in self-field as well as excellent retention of this current in high applied magnetic fields were achieved in the thick films via incorporation of a periodic array of extended columnar defects, composed of self-aligned nanodots of nonsuperconducting material extending through the entire thickness of the film. These columnar defects are highly effective in pinning the superconducting vortices or flux lines, thereby resulting in the substantially enhanced performance of this wire.
RESUMEN
The baculovirus expression vector system is considered to be a safe, powerful, but cell-lytic heterologous protein expression system in insect cells. We show here that there is a new baculovirus system for efficient gene transfer and expression using the popular and genetically well-understood Drosophila S2 cells. The recombinant baculovirus was constructed to carry an enhanced green fluorescent protein under the control of polyhedrin promoter as a fluorescent selection marker in the Sf21 cell line. Recombinant baculoviruses were then used to transduce S2 cells with target gene expression cassettes containing a Drosophila heat shock protein 70, an actin 5C, or a metallothionein promoter. Nearly 100% of the S2 cells showed evidence of gene expression after infection. The time course for the optimal protein expression peaked at 24 to 36 h postinfection, which is significantly earlier than a polyhedrin-driven protein expression in Sf21 cells. Importantly, S2 cells did not appear to be lysed after infection, and the protein expression levels are comparable to those of proteins under the control of polyhedrin promoter in several lepidopteran cell lines. Most surprisingly, S2 cells permit repetitive infections of multiple baculoviruses over time. These findings clearly suggest that this baculovirus-S2 system may effect the efficient gene transfer and expression system of the well-characterized Drosophila S2 cells.
Asunto(s)
Baculoviridae , Drosophila/virología , Vectores Genéticos , Sobreinfección , Transfección , Animales , Células Cultivadas , Regulación Viral de la Expresión Génica , Recombinación GenéticaRESUMEN
A 37-year-old woman with a 10-year history of metastatic carcinoid presented to her oncologist with increased dyspnea. Further evaluation revealed hypoxemia and intrapulmonary vasodilatation. We describe a case of hepatopulmonary-like physiology associated with metastatic carcinoid in a patient with intact liver function. To our knowledge, this is the first documented case of intrapulmonary shunting and hepatopulmonary-like physiology associated with metastatic carcinoid.
Asunto(s)
Tumor Carcinoide/secundario , Síndrome Carcinoide Maligno/fisiopatología , Circulación Pulmonar , Adulto , Femenino , Síndrome Hepatopulmonar/diagnóstico , Síndrome Hepatopulmonar/fisiopatología , Humanos , Neoplasias Hepáticas/secundario , Síndrome Carcinoide Maligno/diagnóstico , VasodilataciónRESUMEN
A 33-year-old man was investigated for dyspnea on exertion and the presence of a pansystolic murmur. Physical examination revealed dextrocardia confirmed by chest radiograph, which also showed oligemic right lung field. Subsequent cardiac catheterization revealed secundum atrial septal defect, persistent left sided superior vena cava, and severe mitral valve prolapse causing severe mitral regurgitation with pulmonary hypertension. The right pulmonary artery was absent. It is the first report of the association between severe mitral valve prolapse and absent right pulmonary artery.