RESUMEN
Cisplatin (CDDP)-based systematic chemotherapy remains the mainstay of treatment for muscle-invasive bladder cancer (MIBC). However, acquired resistance to CDDP, a multifactorial process governed by an array of signals acting at different levels, is the major problem in BC treatment. Here, we report for the first time that, expression of Paired-box gene 5 (PAX5), a B-cell essential transcription factor, was significantly induced in CDDP-resistant BC tissues and in experimentally-induced CDDP-resistant BC cells. Inhibition of PAX5 expression by shRNA treatment effectively improved CDDP sensitivity in BC cells, whereas overexpression of PAX5 potentiated CDDP resistance through supporting BC cell survival. Mechanistically, using luciferase reporter and chromatin immunoprecipitation assays, we identified prostaglandin-endoperoxide synthase 2 (PTGS2, also called COX2), a potent enzyme responsible for prostanoids formation and inflammatory response, as the direct down-stream target of PAX5. PAX5 exerted its oncogenic function during the pathogenesis of CDDP resistance via stimulation of PTGS2 transcription. These observations collectively suggest that dysregulation of PAX5/PTGS2 cascade plays a causal role in the induction of CDDP resistance and gene silencing approaches targeting this pathway may therefore provide a novel therapeutic strategy for overcoming CDDP resistance in BC.
Asunto(s)
Cisplatino/farmacología , Ciclooxigenasa 2/genética , Resistencia a Antineoplásicos/genética , Factor de Transcripción PAX5/genética , Activación Transcripcional , Neoplasias de la Vejiga Urinaria/patología , Humanos , Neoplasias de los Músculos/secundario , Invasividad Neoplásica , Transducción de Señal , Células Tumorales CultivadasRESUMEN
Mechanistic insight into estrogen deficiency by polycystic ovary syndrome (PCOS) remains a longstanding challenge in reproductive medicine. Recent advance suggest that Wingless-type MMTV integration site family members (WNTs), in concert with its Frizzled (FZD) receptors, regulate normal folliculogenesis, luteogenesis and ovarian steroidogenesis. However, no studies have so far investigated any causality between WNT-FZDs interactions and disrupted estrogen synthesis under certain pathological conditions. Here, we show that (i) FZD3 expression was significantly up-regulated in the cumulus cells (CCs) from PCOS patients. This up-regulation, along with the activation of WNT2/ß-Catenin pathway, was tightly associated with insulin resistance and estrogen deficiency, two hallmarks of PCOS. (ii) Overexpression of exogenous FZD3 in human granulosa cell COV434 impaired long-term FSH incubation-induced CYP19A1 transactivation and the recruitment of ß-Catenin onto CYP19A1 promoter, and subsequently compromised FSH-stimulated estrogen production. (iii) Conversely, inhibition of FZD3 expression exhibited a therapeutic effect on estrogen synthesis in PCOS CCs. Thus, excessive FZD3 expression in CCs may act as a brake on steroidogenic activation that is normally overcome by FSH stimulation. Future endeavor in this field should help to elucidate the complicated crosstalk between energy metabolism and endocrine cells through WNT/FZD signaling molecules.
Asunto(s)
Células del Cúmulo/metabolismo , Estrógenos/biosíntesis , Receptores Frizzled/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Vía de Señalización Wnt , Proteína wnt2/metabolismo , beta Catenina/metabolismo , Células Cultivadas , Células del Cúmulo/patología , Regulación hacia Abajo , Femenino , Humanos , Síndrome del Ovario Poliquístico/patologíaRESUMEN
Abnormal perpetual inflammatory response and sequential cytokine-induced prostaglandin E2 (PGE2) play important roles in the pathogenesis of rheumatoid arthritis (RA). The underlying regulatory mechanism, however, remain largely unknown. Here, we discovered that expression level of Metastasis associated protein 1 (MTA1), an important chromatin modifier that plays a critical role in transcriptional regulation by modifying DNA accessibility for cofactors, was upregulated in human rheumatoid synovial tissues. Furthermore, a knockdown of MTA1 by siRNA in the human fibroblast-like synovial cell line MH7A was found to impair the 4-hydroxynonenal (4-HNE)-induced transcriptional expression levels of certain proinflammatory cytokines including IL-1ß, TNF-α and IL-6. Moreover, endogenous MTA1 was required for the cytokines-induced PGE2 synthesis by rheumatoid synoviocytes. Collectively, the coordinated existence of MTA1 inside distinct cascade loops points to its indispensable role in the modulation of the integrated cytokine network along the pathogenesis of RA. Further exploration of the functional details of this master transcriptional regulator should be an attractive strategy to identify novel therapeutic target for RA and warrants execution.
Asunto(s)
Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Dinoprostona/inmunología , Histona Desacetilasas/inmunología , Proteínas Represoras/inmunología , Transducción de Señal , Membrana Sinovial/inmunología , Membrana Sinovial/patología , Aldehídos/inmunología , Artritis Reumatoide/genética , Línea Celular , Citocinas/genética , Citocinas/inmunología , Regulación de la Expresión Génica , Histona Desacetilasas/análisis , Histona Desacetilasas/genética , Humanos , Proteínas Represoras/análisis , Proteínas Represoras/genética , Membrana Sinovial/metabolismo , TransactivadoresAsunto(s)
Neoplasias de Cabeza y Cuello/patología , Lipoma/patología , Neoplasias de los Tejidos Blandos/patología , Antígeno 12E7 , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Moléculas de Adhesión Celular/metabolismo , Diagnóstico Diferencial , Neoplasias de Cabeza y Cuello/metabolismo , Hemangioma/patología , Humanos , Lipoma/metabolismo , Liposarcoma Mixoide/patología , Masculino , Persona de Mediana Edad , Proteínas S100/metabolismo , Neoplasias de los Tejidos Blandos/metabolismoAsunto(s)
Angiomiolipoma/patología , Neoplasias Cutáneas/patología , Actinas/metabolismo , Angiomiolipoma/metabolismo , Angiomiolipoma/cirugía , Desmina/metabolismo , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Neoplasias de Células Epitelioides Perivasculares/metabolismo , Neoplasias de Células Epitelioides Perivasculares/patología , Proteínas S100/metabolismo , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/cirugíaRESUMEN
Members of the Drosophila behavior/human splicing protein family, including splicing factor proline/glutamine rich (SFPQ), non-POU domain-containing octamer-binding protein (NONO), and paraspeckle protein component 1 (PSPC1), are abundantly expressed in testicular Sertoli cells (SCs), but their roles remain obscure. Here, we show that treatment with mono-(2-ethylhexyl) phthalate (MEHP), a well-known SC toxicant, selectively stimulates the expression levels of NONO and PSPC1. Simultaneous inhibition of NONO and PSPC1 expression in SCs enhances MEHP-induced oxidative stress and potentiates SC death. Mechanistically, NONO and PSPC1 transcriptionally activate aldehyde dehydrogenase 1 (Aldh1a1), by synergistically binding to the distinct CCGGAGTC sequence in the Aldh1a1 promoter. Together, the NONO/PSPC1-ALDH1A1 cascade may serve as an indispensable defense mechanism against MEHP insult in SCs.