Transactivation of PTGS2 by PAX5 signaling potentiates cisplatin resistance in muscle-invasive bladder cancer cells.

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.

Deregulation of WNT2/FZD3/ß-catenin pathway compromises the estrogen synthesis in cumulus cells from patients with polycystic ovary syndrome.

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.

Synergistic upregulation of NONO and PSPC1 regulates Sertoli cell response to MEHP via modulation of ALDH1A1 signaling.

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.

Metastasis-associated protein 1 (MTA1) signaling in rheumatoid synovium: Regulation of inflammatory response and cytokine-mediated production of prostaglandin E2 (PGE2).

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.