LncRNAs are reported to participate in neuropathic pain development. LncRNA X-inactive specific transcript (XIST) is involved in the progression of various cancers. However, the role of XIST in neuropathic pain remains unclear. In our present study, we established a chronic constriction injury (CCI) rat model and XIST was found to be greatly upregulated both in the spinal cord tissues and in the isolated microglias of CCI rats. Inhibition of XIST inhibited neuropathic pain behaviors including mechanical and thermal hyperalgesia. Moreover, decrease of XIST repressed neuroinflammation through inhibiting COX-2, tumor necrosis factor (TNF)-α and IL-6 and in CCI rats. Previously, miR-150 has been reported to restrain neuropathic pain by targeting TLR5. Currently, miR-150 was predicted to be a microRNA target of XIST, which indicated a negative correlation between miR-150 and XIST. miR-150 was remarkably decreased in CCI rats and overexpression of miR-150 can significantly suppress neuroinflammation-related cytokines. Furthermore, ZEB1 was exhibited to be a direct target of miR-150 and we found it was overexpressed in CCI rats. Silencing ZEB1 was able to inhibit neuropathic pain in vivo and downreguation of XIST decreased ZEB1, which can be reversed by miR-150 inhibitors. Taken these together, we indicated that XIST can induce neuropathic pain development in CCI rats via upregulating ZEB1 by acting as a sponge of miR-150. It was revealed that XIST/miR-150/ZEB1 axis can be provided as a therapeutic target in neuropathic pain.
Many studies have reported that microRNAs participate in neuropathic pain development. Previously, miR-200b and miR-429 are reported to be involved in various diseases. In our current study, we focused on their roles in neuropathic pain and we found that miR-200b and miR-429 were significantly decreased in chronic constriction injury (CCI) rat spinal cords and isolated microglials. miR-200b and miR-429 overexpression were able to relieve neuropathic pain through modulating PWT and PWL in CCI rats. Meanwhile, we observed that both miR-200b and miR-429 upregulation could repress neuroinflammation via inhibiting inflammatory cytokines such as IL-6, IL-1β, and TNF-α in CCI rats. By carry out bioinformatics technology, Zinc finger E box binding protein-1 (ZEB1) was predicted as target of miR-200b, and miR-429 and dual-luciferase reporter assays confirmed the correlation between them. ZEB1 has been reported to regulate a lot of diseases. Here, we found that ZEB1 was greatly increased in CCI rats and miR-200b and miR-429 overexpression markedly suppressed ZEB1 mRNA expression in rat microglial cells. In addition, knockdown of ZEB1 can reduce neuropathic pain development and co-transfection of LV-anti-miR-200b/miR-429 reversed this phenomenon in vivo. Taken these together, our results suggested that miR-200b/miR-429 can serve as an important regulator of neuropathic pain development by targeting ZEB1.
Background Tumor angiogenesis, an essential process for cancer proliferation and metastasis, has a critical role in prognostic of kidney renal clear cell carcinoma (KIRC), as well as a target in guiding treatment with antiangiogenic agents. However, tumor angiogenesis subtypes and potential epigenetic regulation mechanisms in KIRC patient remains poorly characterized. System evaluation of angiogenesis subtypes in KIRC patient might help to reveal the mechanisms of KIRC and develop more target treatments for patients. Method Ten independent tumor angiogenesis signatures were obtained from molecular signatures database (MSigDB) and gene set variation analysis was performed to calculate the angiogenesis score in silico using the Cancer Genome Atlas (TCGA) KIRC dataset. Tumor angiogenesis subtypes in 539 TCGA-KIRC patients were identified using consensus clustering analysis. The potential regulation mechanisms was studied using gene mutation, copy number variation, and differential methylation analysis (DMA). The master transcription factors (MTF) that cause the difference in tumor angiogenesis signals were completed by transcription factor enrichment analysis. Results The angiogenesis score of a prognosis related angiogenesis signature including 189 genes was significantly correlated with immune score, stroma score, hypoxia score, and vascular endothelial growth factor (VEGF) signal score in 539 TCGA KIRC patients. MMRN2, CLEC14A, ACVRL1, EFNB2, and TEK in candidate gene set showed highest correlation coefficient with angiogenesis score in TCGA-KIRC patients. In addition, all of them were associated with overall survival in both TCGA-KIRC and E-MTAB-1980 KIRC data. Clustering analysis based on 183 genes in angiogenesis signature identified two prognosis related angiogenesis subtypes in TCGA KIRC patients. Two clusters also showed different angiogenesis score, immune score, stroma score, hypoxia score, VEGF signal score, and microenvironment score. DMA identified 59,654 differential methylation sites between two clusters and part of these sites were correlated with tumor angiogenesis genes including CDH13, COL4A3, and RHOB. In addition, RFX2, SOX13, and THRA were identified as top three MTF in regulating angiogenesis signature in KIRC patients. Conclusion Our study indicate that evaluation the angiogenesis subtypes of KIRC based on angiogenesis signature with 183 genes and potential epigenetic mechanisms may help to develop more target treatments for KIRC patients.
Nonobstructive azoospermia (NOA) or testicular failure is the most severe form of male infertility. A variety of conditions, both acquired and congenital, can cause azoospermia. However, in a large number of azoospermia patients who are classified as idiopathic cases, the etiology remains poorly understand mainly due to the lack of knowledge of all the genetic causes and molecular mechanisms responsible for spermatogenesis failure. Identification of the key gene modules and pathways-related spermatogenesis failure might help to reveal the mechanisms of idiopathic azoospermia. Therefore, the expression patterns of spermatogenesis-associated genes in NOA were analyzed by weighted gene coexpression network analysis (WGCNA) based on two public microarray data sets (GSE45885 and GSE45887), which included 51 samples and 32,321 genes. We identified a module (turquoise) that was significantly related to the Johnsen score of the testicular samples. In addition, the results of function and pathway enrichment analyses based on the online bioinformatics database Metascape revealed that genes in the turquoise module were mainly related to the process of spermatogenesis and spermatid development. To further identify spermatogenesis-associated genes, a microarray data set (GSE926) of murine testis at different developmental time points was analyzed by WGCNA. The blue module in GSE926 was significantly related to the time of murine testis development. The overlap study and k-core analysis based on protein-protein interaction network revealed that spermatogenesis-and spermatid development-associated genes, including glyceraldehyde-3-phosphate dehydrogenase, ADAM metallopeptidase domain 2, transition protein 1, testis-specific serine kinase 2, transition protein 2, and germ cell-associated 1 (GSG1), were further identified in the selected modules. The expression profile of GSG1 in human testis was chosen for further study using immunochemistry staining. Taken together, these screened gene modules and pathways provided a more detailed genetic and molecular mechanism underlying spermatogenesis failure occurrence and holds promise as potential diagnosis biomarkers and therapeutic targets.
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