RESUMEN
The androgen receptor (AR) pathway is critical for prostate cancer carcinogenesis and development; however, after 18-24 months of AR blocking therapy, patients invariably progress to castration-resistant prostate cancer (CRPC), which remains an urgent problem to be solved. Therefore, finding key molecules that interact with AR as novel strategies to treat prostate cancer and even CRPC is desperately needed. In the current study, we focused on the regulation of RNA-binding proteins (RBPs) associated with AR and determined that the mRNA and protein levels of AR were highly correlated with Musashi2 (MSI2) levels. MSI2 was upregulated in prostate cancer specimens and significantly correlated with advanced tumor grades. Downregulation of MSI2 in both androgen sensitive and insensitive prostate cancer cells inhibited tumor formation in vivo and decreased cell growth in vitro, which could be reversed by AR overexpression. Mechanistically, MSI2 directly bound to the 3'-untranslated region (UTR) of AR mRNA to increase its stability and, thus, enhanced its transcriptional activity. Our findings illustrate a previously unknown regulatory mechanism in prostate cancer cell proliferation regulated by the MSI2-AR axis and provide novel evidence towards a strategy against prostate cancer.
Asunto(s)
Neoplasias de la Próstata/patología , Proteínas de Unión al ARN/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Regiones no Traducidas 3' , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Clasificación del Tumor , Trasplante de Neoplasias , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Estabilidad del ARN , Receptores Androgénicos/química , Regulación hacia ArribaRESUMEN
Recent studies have demonstrated that ubiquitin-specific protease 10 (USP10) plays a catalytic role in tumour suppression mainly by deubiquitinating its target proteins to enhance their stabilities. However, we found that USP10 could interact with and regulate the expression of oncogenic factor Musashi-2 (MSI2). We investigated whether USP10 positively regulates the expression of MSI2 by deubiquitination and confirmed the type of polyubiquitin chain that is linked to MSI2. We also explored the role of USP10 in regulating the proliferation of colon cancer through different experiments. This study provides a completely new perspective in understanding the role of USP10 in deubiquitination. In the future, USP10 may serve as a target for colon cancer treatment.
Asunto(s)
Neoplasias del Colon/metabolismo , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/metabolismo , Ubiquitina Tiolesterasa/metabolismo , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular , Neoplasias del Colon/genética , Regulación Neoplásica de la Expresión Génica , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Lisina , Estabilidad Proteica , Proteínas de Unión al ARN/genética , Ubiquitina Tiolesterasa/genética , Ubiquitinación , Regulación hacia ArribaRESUMEN
PURPOSE: Recent studies have determined that cartilage oligomeric matrix protein (COMP) plays a vital role in carcinogenesis. We sought to clarify the role of COMP in colon cancer. METHODS: We investigated gene expression data from The Cancer Genome Atlas (TCGA) dataset. Tissue microarrays (TMA) containing paired samples from 253 patients with colon cancer were subjected to immunostaining. COMP levels in serum of colon cancer patients and healthy donors were measured with ELISA. We established COMP-knockout cells using the CRISPR/Cas9 system and COMP-overexpressing cells using lentiviral vectors to detect the effects of COMP on colon cancer cells using Cell Counting Kit-8 (CCK8), colony formation, apoptosis detection kit, and tumorigenesis assays in nude mice. RESULTS: The analysis of TCGA dataset and the results of the TMA suggested that COMP expression levels were significantly higher in cancer tissues than in adjacent normal tissues. Moreover, high COMP expression was correlated with the poor outcome of colon cancer patients. COMP levels in the sera of preoperative patients with colon cancer were much higher than those in healthy donors and were significantly reduced after colectomy. Colon cancer cells without COMP were defective with respect to the ability to proliferate, colony formation, the ability to resist 5-Fluorouracil-induced apoptosis and the growth of xenograft tumors in mice. Contrasting results were observed in COMP overexpressed cells. COMP promoted colon cancer cell proliferation partially through the activation of PI3K/ Akt/ mTOR/ p70S6K pathway. CONCLUSIONS: COMP may be a novel prognostic indicator and biomarker and also a potential therapeutic target for colon cancer.
Asunto(s)
Proteína de la Matriz Oligomérica del Cartílago/biosíntesis , Neoplasias del Colon/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Anciano , Animales , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Células CACO-2 , Proteína de la Matriz Oligomérica del Cartílago/sangre , Proteína de la Matriz Oligomérica del Cartílago/genética , Línea Celular Tumoral , Proliferación Celular/fisiología , Neoplasias del Colon/sangre , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Bases de Datos Genéticas , Supervivencia sin Enfermedad , Femenino , Células HCT116 , Células HEK293 , Células HT29 , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Estadificación de Neoplasias , Transducción de Señal , Tasa de Supervivencia , Análisis de Matrices Tisulares , Transcriptoma , Regulación hacia ArribaRESUMEN
A new photonic bandgap (PBG) cover for a patch antenna with a photonic bandgap substrate is introduced. The plane wave expansion method and the FDTD method were used to calculate such an antenna system. Numerical results for the input return loss, radiation pattern, surface wave, and the directivity of the antennas are presented. A comparison between the conventional patch antenna and the new PBG antenna is given. It is shown that the new PBG cover is very efficient for improving the radiation directivity. The physical reasons for the improvement are also given.