AIMTo investigate the role of tumor microenvironment (TME)-related long non-coding RNA (lncRNA) in uveal melanoma (UM), probable prognostic signature and potential small molecule drugs using bioinformatics analysis.METHODSUM expression profile data were downloaded from the Cancer Genome Atlas (TCGA) and bioinformatics methods were used to find prognostic lncRNAs related to UM immune cell infiltration. The gene expression profile data of 80 TCGA specimens were analyzed using the single sample Gene Set Enrichment Analysis (ssGSEA) method, and the immune cell infiltration of a single specimen was evaluated. Finally, the specimens were divided into high and low infiltration groups. The differential expression between the two groups was analyzed using the R package 'edgeR'. Univariate, multivariate and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analyses were performed to explore the prognostic value of TME-related lncRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses were also performed. The Connectivity Map (CMap) data set was used to screen molecular drugs that may treat UM.RESULTSA total of 2393 differentially expressed genes were identified and met the criteria for the low and high immune cell infiltration groups. Univariate Cox analysis of lncRNA genes with differential expression identified 186 genes associated with prognosis. Eight prognostic markers of TME-included lncRNA genes were established as potentially independent prognostic elements. Among 269 differentially expressed lncRNAs, 69 were up-regulated and 200 were down-regulated. Univariate Cox regression analysis of the risk indicators and clinical characteristics of the 8 lncRNA gene constructs showed that age, TNM stage, tumor base diameter, and low and high risk indices had significant prognostic value. We screened the potential small-molecule drugs for UM, including W-13, AH-6809 and Imatinib.CONCLUSIONThe prognostic markers identified in this study are reliable biomarkers of UM. This study expands our current understanding of the role of TME-related lncRNAs in UM genesis, which may lay the foundations for future treatment of this disease.

01 May 2016·Journal of Neuroscience ResearchQ3 · MEDICINE

Calmodulin activity regulates group I metabotropic glutamate receptor‐mediated signal transduction and synaptic depression

Q3 · MEDICINE

Article

Author: Sethna, Ferzin ; Wang, Hongbing ; Klann, Eric ; Kaphzan, Hanoch ; Zhang, Ming ; Cox, Charles L. ; Autio, Dawn

Group I metabotropic glutamate receptors (mGluR), including mGluR1 and mGluR 5 (mGluR1/5), are coupled to Gq and modulate activity‐dependent synaptic plasticity. Direct activation of mGluR1/5 causes protein translation‐dependent long‐term depression (LTD). Although it has been established that intracellular Ca2+ and the Gq‐regulated signaling molecules are required for mGluR1/5 LTD, whether and how Ca2+ regulates Gq signaling and upregulation of protein expression remain unknown. Through pharmacological inhibition, we tested the function of the Ca2+ sensor calmodulin (CaM) in intracellular signaling triggered by the activation of mGluR1/5. CaM inhibitor N‐[4‐aminobutyl]‐5‐chloro‐2‐naphthalenesulfonamide hydrochloride (W13) suppressed the mGluR1/5‐stimulated activation of extracellular signal‐regulated kinase 1/2 (ERK1/2) and p70‐S6 kinase 1 (S6K1) in hippocampal neurons. W13 also blocked the mGluR1/5 agonist‐induced synaptic depression in hippocampal slices and in anesthetized mice. Consistent with the function of CaM, inhibiting the downstream targets Ca2+/CaM‐dependent protein kinases (CaMK) blocked ERK1/2 and S6K1 activation. Furthermore, disruption of the CaM–CaMK–ERK1/2 signaling cascade suppressed the mGluR1/5‐stimulated upregulation of Arc expression. Altogether, our data suggest CaM as a new Gq signaling component for coupling Ca2+ and protein upregulation and regulating mGluR1/5‐mediated synaptic modification. © 2016 Wiley Periodicals, Inc.

01 Feb 2009·Journal of Neuroscience ResearchQ3 · MEDICINE

Regulation of brain‐derived neurotrophic factor‐mediated transcription of the immediate early gene Arc by intracellular calcium and calmodulin

Q3 · MEDICINE

Article

Author: Yongneng Luo ; Fei Zheng ; Hongbing Wang

AbstractThe induction of the immediate early gene Arc is strongly implicated in synaptic plasticity. Although the role of ERK has been demonstrated, the regulation of Arc expression is largely unknown. In this study, we investigated the major signaling pathways underlying brain‐derived neurotrophic factor (BDNF)‐mediated Arc transcription in cultured cortical neurons. The BDNF‐stimulated Arc transcription was regulated solely by the Ras‐Raf‐MAPK signaling through ERK, but not by phosphoinositide 3‐kinase (PI3K) and PLC‐γ activities. Although it was demonstrated that BDNF might promote calcium entry through calcium channels and NMDA receptors, chelating extracellular calcium with EGTA failed to block Arc transcription. In contrast, chelating intracellular calcium ([Ca2+]i) by BAPTA‐AM abolished BDNF‐mediated Arc up‐regulation. Surprisingly, BAPTA‐AM did not block ERK activation, indicating that [Ca2+]i and Ras‐Raf‐MAPK are not coupled, and the activation of ERK alone is not sufficient to up‐regulate Arc transcription. Moreover, we found that inhibition of calmodulin (CaM) by W13 blocked both Arc transcription and ERK activation, revealing a Ca2+‐independent function of CaM. These data suggested novel functions of [Ca2+]i and CaM in BDNF signaling. Comparison of the Arc transcription profiles between Ca2+‐stimulated and BDNF‐stimulated neurons demonstrated that the regulatory mechanisms were distinctively tailored to the complex features of neuronal activity. Specifically, PI3K and CaM‐dependent protein kinase (CaMK) activity were required for Ca2+‐stimulated Arc transcription through regulating ERK signaling. Such cross‐talks between PI3K, CaMK, and ERK was absent in BDNF‐stimulated neurons. © 2008 Wiley‐Liss, Inc.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	CN	Zhengzhou University	05 Feb 2024

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