RESUMEN
Breast cancer is the most frequently diagnosed life-threatening cancer in women. Triple-negative breast cancer (TNBC) has an aggressive clinical behavior, but the treatment of TNBC remains challenging. MicroRNAs (miRNAs) have emerged as a potential target for the diagnosis, therapy and prognosis of breast cancer. However, the precise role of miRNAs and their targets in breast cancer remain to be elucidated. Here we show that miR-218 is downregulated and miR-129 is upregulated in TNBC samples and their expressions confer prognosis to patients. Gain-of-function and loss-of-function analysis reveals that miR-218 has a tumor suppressive activity, while miR-129 acts as an oncomir in breast cancer. Notably, miR-218 and miR-129 directly target Lamin B1 and Lamin A, respectively, which are also found to be deregulated in human breast tumors. Finally, we demonstrate Lamins as the major factors in reliable miR-218 and miR-129 functions for breast cancer progression. Our findings uncover a new miRNA-mediated regulatory network for different Lamins and provide a potential therapeutic target for breast cancer.
Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Regulación Neoplásica de la Expresión Génica , Laminas/metabolismo , MicroARNs/metabolismo , Proliferación Celular , Humanos , Células MCF-7 , Invasividad Neoplásica/patologíaRESUMEN
Ubiquitin-conjugating enzyme E2O (UBE2O) is expressed preferentially in metabolic tissues, but its role in regulating energy homeostasis has yet to be defined. Here we find that UBE2O is markedly upregulated in obese subjects with type 2 diabetes and show that whole-body disruption of Ube2o in mouse models in vivo results in improved metabolic profiles and resistance to high-fat diet-induced (HFD-induced) obesity and metabolic syndrome. With no difference in nutrient intake, Ube2o-/- mice were leaner and expended more energy than WT mice. In addition, hyperinsulinemic-euglycemic clamp studies revealed that Ube2o-/- mice were profoundly insulin sensitive. Through phenotype analysis of HFD mice with muscle-, fat-, or liver-specific knockout of Ube2o, we further identified UBE2O as an essential regulator of glucose and lipid metabolism programs in skeletal muscle, but not in adipose or liver tissue. Mechanistically, UBE2O acted as a ubiquitin ligase and targeted AMPKα2 for ubiquitin-dependent degradation in skeletal muscle; further, muscle-specific heterozygous knockout of Prkaa2 ablated UBE2O-controlled metabolic processes. These results identify the UBE2O/AMPKα2 axis as both a potent regulator of metabolic homeostasis in skeletal muscle and a therapeutic target in the treatment of diabetes and metabolic disorders.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina , Síndrome Metabólico/metabolismo , Obesidad/metabolismo , Enzimas Ubiquitina-Conjugadoras/metabolismo , Animales , Línea Celular , Diabetes Mellitus Tipo 2/complicaciones , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Femenino , Glucosa/metabolismo , Humanos , Insulina/metabolismo , Metabolismo de los Lípidos , Masculino , Síndrome Metabólico/etiología , Ratones , Ratones Noqueados , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Mioblastos Esqueléticos , Obesidad/etiología , Cultivo Primario de Células , Proteolisis , Enzimas Ubiquitina-Conjugadoras/análisis , Enzimas Ubiquitina-Conjugadoras/genética , Ubiquitinación , Regulación hacia ArribaRESUMEN
PTEN is a lipid phosphatase that antagonizes the PI3K/AKT pathway and is recognized as a major dose-dependent tumor suppressor. The cellular mechanisms that control PTEN levels therefore offer potential routes to therapy, but these are as yet poorly defined. Here we demonstrate that PTEN plays an unexpected role in regulating its own stability through the transcriptional upregulation of the deubiquitinase USP11 by the PI3K/FOXO pathway, and further show that this feedforward mechanism is implicated in its tumor-suppressive role, as mice lacking Usp11 display increased susceptibility to PTEN-dependent tumor initiation, growth and metastasis. Notably, USP11 is downregulated in cancer patients, and correlates with PTEN expression and FOXO nuclear localization. Our findings therefore demonstrate that PTEN-PI3K-FOXO-USP11 constitute the regulatory feedforward loop that improves the stability and tumor suppressive activity of PTEN.
Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Tioléster Hidrolasas/metabolismo , Animales , Células Cultivadas , Factores de Transcripción Forkhead/genética , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Noqueados , Ratones Desnudos , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/genética , Transducción de Señal/genética , Transducción de Señal/fisiología , Tioléster Hidrolasas/genéticaRESUMEN
Myeloid malignancies, including myelodysplastic syndromes and acute myeloid leukemia, are clonal diseases arising in hematopoietic stem or progenitor cells. In recent years, microRNA (miRNA) expression profiling studies have revealed close associations of miRNAs with cytogenetic and molecular subtypes of myeloid malignancies, as well as outcome and prognosis of patients. However, the roles of miRNA deregulation in the pathogenesis of myeloid malignancies and how they cooperate with protein-coding gene variants in pathological mechanisms leading to the diseases have not yet been fully understood. In this review, we focus on recent insights into the role of miRNAs in the development and progression of myeloid malignant diseases and discuss the prospect that miRNAs may serve as a potential therapeutic target for leukemia.