The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression
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ABSTRACT:
PROVIDER: PRJNA841834 | ENA |
REPOSITORIES: ENA
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Project description:Transient receptor potential channel TRPM2 is highly expressed in many cancers and involved in regulation of key physiological processes including mitochondrial function, bioenergetics, and oxidative stress. In Stage 4 non-MYCN amplified neuroblastoma patients, high TRPM2 expression is associated with worse outcome. Here, neuroblastoma cells with high TRPM2 expression demonstrated increased migration and invasion capability. RNA sequencing, RT-qPCR, and Western blotting demonstrated that the mechanism involved significantly greater expression of integrins α1, αv, β1, and β5 in cells with high TRPM2 expression. Transcription factors HIF-1α, E2F1, and FOXM1, which bind promoter/enhancer regions of these integrins, were increased in cells with high TRPM2 expression. Subcellular fractionation confirmed high levels of α1, αv, and β1 membrane localization and co-immunoprecipitation confirmed the presence of α1β1, αvβ1, and αvβ5 complexes. Inhibitors of α1β1, αvβ1, and αvβ5 complexes significantly reduced migration and invasion in cells highly expressing TRPM2, confirming their functional role. Increased pAktSer473 and pERKThr202/Tyr204, which promote migration through mechanisms including integrin activation, were found in cells highly expressing TRPM2. TRPM2 promotes migration and invasion in neuroblastoma cells highly expressing TRPM2 through modulation of integrins together with enhancing cell survival, negatively affecting patient outcome and providing the rationale for TRPM2 inhibition in anti-neoplastic therapy.
2022-05-27 | GSE203660 | GEO
Project description:Transient receptor potential channel melastatin 2 (TRPM2) is highly expressed in cancer and has an essential function in preserving viability through maintenance of mitochondrial function and antioxidant response. Here, the role of TRPM2 in cell survival was examined in neuroblastoma cells deleted of TRPM2 with CRISPR technology. Viability was significantly decreased in TRPM2 knockout after doxorubicin treatment. RNA sequence analysis and RT-qPCR revealed reduced RNAs encoding master transcription regulators FOXM1 and E2F1/2 and downstream cell cycle targets including Cyclin B1, CDK1, PLK1, and CKS1. CHIP analysis demonstrated decreased FOXM1 binding to their promoters. Western blotting confirmed decreased expression, and increased expression of CDK inhibitor p21, a CKS1 target. In cells with TRPM2 deletion, cell cycle progression to S and G2/M phases was reduced after treatment with doxorubicin. RNA sequencing also identified decreased DNA repair proteins in cells with TRPM2 deletion after doxorubicin treatment, and DNA damage was increased. Wild type TRPM2 but not Ca2+-impermeable mutant E960D, restored live cell number and reconstituted expression of E2F1, FOXM1, and cell cycle/DNA repair proteins. FOXM1 expression alone restored viability. TRPM2 is a potential therapeutic target to reduce tumor proliferation and increase doxorubicin sensitivity through modulation of FOXM1, E2F1, and cell cycle/DNA repair proteins.
2022-02-25 | GSE197243 | GEO
Project description:The human ion channel TRPM2 modulates cell survival in neuroblastoma through E2F1 and FOXM1
| PRJNA809423 | ENA
Project description:High serum concentrations of kidney-derived protein uromodulin (Tamm-Horsfall protein or THP) have recently been shown to be independently associated with low mortality in both older adults and cardiac patients, but the underlying mechanism remains unclear. Here, we show that THP inhibits the generation of reactive oxygen species (ROS) both in the kidney and systemically. Consistent with this experimental data, the concentration of circulating THP in patients with surgery-induced acute kidney injury (AKI) correlated with systemic oxidative damage. THP in the serum dropped after AKI, and was associated with an increase in systemic ROS. The increase in oxidant injury correlated with post-surgical mortality and need for dialysis. Mechanistically, THP inhibited the activation of the TRPM2 channel. Furthermore, inhibition of TRPM2 in vivo in a mouse model, mitigated the systemic increase in ROS during AKI and THP deficiency. Our results suggest that THP is a key regulator of systemic oxidative stress by suppressing TRPM2 activity and our findings might help to explain how circulating THP deficiency is linked with poor outcomes and increased mortality.
2019-10-11 | GSE136219 | GEO
Project description:There is overwhelming evidence indicating that human cancer is a genetic disease caused by sequential accumulation of mutations in oncogenes and tumor suppressor genes. However, it is also increasingly apparent that cancer depends not only on mutations in these coding genes, but also on alterations in the large class of the non-coding RNAs (ncRNAs). Here, we report that one such long ncRNA, TRPM2-AS, an antisense transcript in respect to TRPM2, a gene encoding for a ion channel activated by oxidative stress, is significantly overexpressed in prostate cancer. High expression levels of either TRPM2-AS or of a related gene signature are linked to poor clinical outcome, with the related gene signature working also independently of the patient's Gleason score. Moreover, TRPM2-AS knock-out leads to apoptosis of prostate cancer cells, with transcriptional profiling indicating an unbearable increase of cellular stress in dying cells, coupled to the down-regulation of several already known oncological targets. Considering that TRPM2-AS transcripts are barely detectable in healthy cells, these data strongly suggest that it, beside being a novel prognostic marker, is also a suitable therapeutic target in prostate cancer and establish a strong rationale for developing agents targeting either its expression or the expression of molecules in its pathway. PC3 cells were transfeted either a non-specific siRNA or with a TRPM2-AS siRNA in replicates. Cells were grown for 48 hours, then were harvested and RNA was isolated
2014-09-01 | E-GEOD-40687 | biostudies-arrayexpress
Project description:There is overwhelming evidence indicating that human cancer is a genetic disease caused by sequential accumulation of mutations in oncogenes and tumor suppressor genes. However, it is also increasingly apparent that cancer depends not only on mutations in these coding genes, but also on alterations in the large class of the non-coding RNAs (ncRNAs). Here, we report that one such long ncRNA, TRPM2-AS, an antisense transcript in respect to TRPM2, a gene encoding for a ion channel activated by oxidative stress, is significantly overexpressed in prostate cancer. High expression levels of either TRPM2-AS or of a related gene signature are linked to poor clinical outcome, with the related gene signature working also independently of the patient's Gleason score. Moreover, TRPM2-AS knock-out leads to apoptosis of prostate cancer cells, with transcriptional profiling indicating an unbearable increase of cellular stress in dying cells, coupled to the down-regulation of several already known oncological targets. Considering that TRPM2-AS transcripts are barely detectable in healthy cells, these data strongly suggest that it, beside being a novel prognostic marker, is also a suitable therapeutic target in prostate cancer and establish a strong rationale for developing agents targeting either its expression or the expression of molecules in its pathway.
2014-09-01 | GSE40687 | GEO
Project description:Circulating Uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel
| PRJNA561615 | ENA
Project description: Not available
| S-EPMC6414629 | biostudies-literature
Project description:Ion channels play critical roles in the physiology and function of the nervous system and contractile tissue; however, their role in non-contractile tissue and embryonic development has yet to be understood. Tracheobronchomalacia (TBM) and complete tracheal rings (CTR) are disorders affecting the muscle and cartilage of the trachea and bronchi, whose etiology remains poorly understood. We demonstrated that trachealis muscle organization and polarity are disrupted after epithelial ablation of Wls, a cargo receptor critical for the Wnt signaling pathway, in developing trachea. The phenotype resembles the anomalous trachealis muscle observed after deletion of ion channel encoding genes in developing mouse trachea. We sought to investigate whether and how the deletion ofWlsaffects ion channels during tracheal development. We hypothesize that Wnt signaling influences the expression of ion channels to promote trachealis muscle cell assembly and patterning. Deleting Wls in developing trachea causes differential regulation of genes mediating actin binding, cytoskeleton organization, and potassium ion channel activity. Wnt signaling regulated expression of Kcnj13, Kcnd3, Kcnj8, and Abcc9 as demonstrated by in vitro studies and in vivo analysis in Wnt5a and b-catenin deficient tracheas. Pharmacological inhibition of potassium ion channels and Wnt signaling impaired contractility of developing trachealis smooth muscle and formation of cartilaginous mesenchymal condensation. Thus, in mice, epithelial-induced Wnt/b-catenin signaling mediates trachealis muscle and cartilage development via modulation of ion channel expression, promoting trachealis muscle architecture, contractility, and cartilaginous extracellular matrix. In turn, ion channel activity may influence tracheal morphogenesis underlying TBM and CTR.
2023-11-06 | GSE241175 | GEO
Project description:Tissue stiffening is a physical hallmark of solid tumor. In our study, we found that the mechanosensitive ion channel PIEZO1 can be tumor cells force sensor and transducer that regulate the altered tissue mechanics. We examined the transcriptional changes modulated by depletion of PIEZO1 in two human GBM cell lines. We found that with PIEZO1 KD, the components involved in ECM organization, focal adhesion formation, cytoskeleton, and mitosis, which contribute to tissue stiffness, are down-regulated.
2018-10-18 | GSE113261 | GEO