The E26 transformation-specific (ETS) variant 2 (ETV2) protein, also designated as ETS-related 71, is a member of the ETS transcription factor family and is essential for blood and vascular development in the embryo. The role of ETV2 in cancer has not yet been investigated. In the present study, the expression of ETV2 mRNA was identified in a variety of tumor types, including prostate carcinoma. In addition, ETV2 gene amplification was identified in several types of cancer, suggesting that ETV2 plays an oncogenic role in tumorigenesis. It was demonstrated that ETV2 forms complexes with two histone demethylases: Jumonji domain‑containing (JMJD)2A and JMJD2D; JMJD2A has been previously reported as a driver of prostate cancer development. In the present study, it was reported that ETV2 exhibited the potential to stimulate the promoters of matrix metalloproteinases (MMPs), including MMP1 and MMP7, within LNCaP prostate cancer cells. JMJD2A and JMJD2D could synergize with ETV2 to activate the MMP1 promoter, whereas only JMJD2A stimulated the MMP7 promoter in cooperation with ETV2. Furthermore, ETV2 expression was positively associated with JMJD2A and JMJD2D mRNA levels in neuroendocrine prostate tumors, in which an ETV2 gene amplification rate of 17.8% was identified. Collectively, the results of the present study indicated that ETV2, JMJD2A and JMJD2D may jointly promote tumorigenesis, particularly neuroendocrine prostate tumors. In addition, the interaction with the JMJD2A and JMJD2D epigenetic regulators may be important in the ability of ETV2 to reprogram cells, modulate normal and cancer stem cells, and affect spermatogenesis.
Background OnabotulinumtoxinA (onabotA) is approved globally for prevention of chronic migraine; however, the classical mechanism of action of onabotA in motor and autonomic neurons cannot fully explain the effectiveness of onabotulinumtoxinA in this sensory neurological disease. We sought to explore the direct effects of onabotulinumtoxinA on mouse trigeminal ganglion sensory neurons using an inflammatory soup-based model of sensitization. Methods Primary cultured trigeminal ganglion neurons were pre-treated with inflammatory soup, then treated with onabotulinumtoxinA (2.75 pM). Treated neurons were used to examine transient receptor potential vanilloid subtype 1 and transient receptor potential ankyrin 1 cell-surface expression, calcium influx, and neuropeptide release. Results We found that onabotulinumtoxinA cleaved synaptosomal-associated protein-25 kDa in cultured trigeminal ganglion neurons; synaptosomal-associated protein-25 kDa cleavage was enhanced by inflammatory soup pre-treatment, suggesting greater uptake of toxin under sensitized conditions. OnabotulinumtoxinA also prevented inflammatory soup-mediated increases in TRPV1 and TRPA1 cell-surface expression, without significantly altering TRPV1 or TRPA1 protein expression in unsensitized conditions. We observed similar inhibitory effects of onabotulinumtoxinA on TRP-mediated calcium influx and TRPV1- and TRPA1-mediated release of calcitonin gene-related peptide and prostaglandin 2 under sensitized, but not unsensitized control, conditions. Conclusions Our data deepen the understanding of the sensory mechanism of action of onabotulinumtoxinA and support the notion that, once endocytosed, the cytosolic light chain of onabotulinumtoxinA cleaves synaptosomal-associated protein-25 kDa to prevent soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated processes more generally in motor, autonomic, and sensory neurons.
Skin inflammation is an evolutionary-honed protective mechanism that serves to clear noxious cues and irritants and initiate regeneration. Calcium-permeable transient-receptor-potential (TRP) ion channels have critical functions in sensory transduction which is sensitized in skin inflammation. Skin sensory transduction relies on skin-innervating sensory neurons in the dorsal root ganglion (DRG), but also on innervated keratinocytes (KC). The multimodally-activated TRPV4 is robustly expressed in KC, where it can readily be activated by Ultraviolet-B (UVB). Our goal was to deconstruct keratinocyte TRPV4-mediated signaling, specifically how TRPV4 can facilitate inflammatory injury, thus lowering pain thresholds and rendering KC into pain-generator cells. We wanted to uncover the effect of TRPV4-mediated signaling on UVB-induced inflammasome activation in KC given the powerful impact of the activated inflammasome on pro-inflammatory/pro-algesic secretory signaling from KC to innervating DRG neurons, using mouse models and cultured human KC. In mice, our evidence suggests that TRPV4 functions as calcium-permeable channel upstream of the KC inflammasome. Furthermore, we found that UVB induced activation of TRPV4 caused rapid - within minutes - ERK phosphorylation, caspase-1 activation and IL1ß secretion. In human primary KC we demonstrated that UVB induced secretion of IL1ß was dependent on the NLRP1 inflammasome. Direct chemical TRPV4 activation could also activate NLRP1 and to lesser extent NLPR3. Building on our previous work, we now define at increased resolution TPRV4-dependent forefront signaling mechanisms in KC in response to UVB, showing TRPV4 upstream of the NLRP1 inflammasome in KC, subsequent rapid MAPK ERK activation and pro-inflammatory/pro-algesic secretory function.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.