Deregulated miR‐155 promotes Fas‐mediated apoptosis in human intervertebral disc degeneration by targeting FADD and caspase‐3

Wang, Hai-Qiang; Yu, Xiuping; Liu, Zhi-Heng; Cheng, Xin; Samartzis, D; Jia, Lintao; Wu, Sihan; Huang, Jing; Chen, Jing; Luo, Zhuojing

doi:10.1002/path.2931

Cited by 192 publications

(185 citation statements)

References 47 publications

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“…There is an age gap between patients and controls in this study. As in previous studies concerning the role of miRNA in IDD, (21,22,38) an age gap between patients and controls was also observed. However, the effect of age gap on miRNA levels was not investigated.…”

Section: Discussionsupporting

confidence: 80%

“…(19,20) Of note, miRNAs have been implicated in apoptosis of nucleus pulposus (NP) cells, control of NP cell proliferation, and collagen loss in NP cell. (21)(22)(23) Here, we sought to understand the role of miRNAs in IL-6-induced IDD. NP cells play an important role in maintaining the integrity of the intervertebral disc through their role in producing type II collagen, aggrecan, and other components of ECM.…”

Section: Introductionmentioning

confidence: 99%

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Dysregulated miR-98 Contributes to Extracellular Matrix Degradation by Targeting IL-6/STAT3 Signaling Pathway in Human Intervertebral Disc Degeneration

Lü

Shi

et al. 2015

Journal of Bone and Mineral Research

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Intervertebral disc degeneration (IDD) is associated with dysregulated expression of microRNAs (miRNAs). However, the precise molecular mechanisms underlying this disorder remain unclear. Therefore, we tested the hypothesis that miRNAs modulate IDD through effects on the IL-6/STAT3 signaling pathway, a potential regulator of IDD. The miRNA expression profile was determined in nucleus pulposus (NP) tissues from patients with IDD and controls, employing miRNA microarray and quantitative real-time PCR (RTqPCR). Biological functions of differential expression miRNAs were further investigated using immunofluorescent staining. Luciferase reporter assays and Western blotting were performed to determine miRNA targets. We identified 41 miRNAs that were differentially expressed in patients compared with controls. Following RT-qPCR confirmation, miR-98 was significantly downregulated in degenerative NP tissues. Moreover, its level was inversely correlated with grade of disc degeneration. Through gain-of-function and loss-of-function studies, miR-98 was shown to significantly promote type II collagen expression in NP cells. Interleukin-6 (IL-6) was identified as a target of miR-98. Knockdown of IL-6 induced effects on NP cells similar to those induced by miR-98. In contrast, IL-6 treatment abrogated the effects induced by miR-98 upregulation. Moreover, miR-98 dramatically suppressed expression of STAT3 target gene, MMP2. IL-6 treatment antagonized this effect, whereas knockdown of IL-6 by IL-6 short hairpin RNA (shIL-6) induced inhibitory effects on the expression of p-STAT3 and its main target genes, similar to miR-98. The mRNA level of IL-6 was inversely correlated with that of miR-98 in degenerative NP tissues. These results suggest the downregulation of miR-98 could promote IDD through the IL-6/STAT3 signaling pathway. Our findings also highlight miR-98 as a novel hopeful therapeutic target for IDD.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Dysregulated miR-98 Contributes to Extracellular Matrix Degradation by Targeting IL-6/STAT3 Signaling Pathway in Human Intervertebral Disc Degeneration

Lü

Shi

et al. 2015

Journal of Bone and Mineral Research

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“…Microarray datasets of GSE19943 (19), GSE15227 (20) and GSE34095 (21) were downloaded from the National Center of Biotechnology Information (NCBI), Gene Expression Omnibus (GEO) database (http://www.ncbi. nlm.nih.gov/geo/).…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, Tang et al (8) demonstrated that differentially expressed genes (DEGs) identified in degenerative disc tissue samples were mainly associated with transforming growth factor-β and the ECM. Furthermore, Wang et al (19) reported that deregulated miR-155 could promote Fas-mediated apoptosis in human IDD by targeting Fas-associated death domain-containing protein (FADD) and caspase-3. In the present study, 3 microarray datasets were integrated and microarray analysis was used to identify the DEGs, grade-specific genes and differentially expressed miRNAs in the IDD samples compared with their corresponding controls.…”

Section: Introductionmentioning

confidence: 99%

Identification of the potential molecular targets for human intervertebral disc degeneration based on bioinformatic methods

Xue

Liu

et al. 2015

International Journal of Molecular Medicine

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Abstract. The present study aimed to explore potential molecular targets and gain further insights into the mechanism of intervertebral disc degeneration (IDD) progression. Microarray datasets of GSE19943, GSE15227 and GSE34095 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) in 3 IDD specimens compared with 3 controls in GSE34095, DEGs in 7 grade III and 3 grade IV samples compared with 5 grade II samples in GSE19943, and differentially expressed miRNAs in 3 degenerated samples compared with 3 controls in GSE15227 were screened. Grade III-and IV-specific networks were constructed and grade-specific genes were extracted. The network features were analyzed, followed by Gene Ontology (GO) enrichment analysis and pathway enrichment analysis of grade-specific genes and DEGs identified in GSE34095. Furthermore, miRNA-pathway interactions were analyzed using Fisher's exact test. Tumor protein p53 (TP53) was a hub gene in the grade III-specific network and ubiquitin C (UBC) was identified to be a hub gene in the grade IV-specific network. Six significant features were identified by grade-specific network topology analysis. Grade-specific genes and DEGs were involved in different GO terms and pathways. Differentially expressed miRNAs were identified to participate in 35 pathways, among which 6 pathways were significantly enriched by DEGs, including apoptosis. The present study identified that key genes (TP53 and UBC) and miR-129-5p may participate in the mechanism of IDD progression. Thus, they may be potential therapeutic targets for IDD.

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“…The role of abnormal expression of miRNAs in the cartilage endplate and cervical or lumbar degeneration has been studied previously; for example, Chen et al (23) reported that miR-34a regulated the apoptosis of cartilage endplate cells by targeting Bcl-2. In addition, Wang et al (34) reported that miR-155 regulated Fas-mediated apoptosis of lumbar nucleus pulposus through FADD and caspase-3. These results suggest that miRNA-mediated apoptosis may serve an important role in cervical/lumbar degeneration.…”

Section: Discussionmentioning

confidence: 99%

Expression of miR-625 and Fas in cervical vertebral cartilage endplate

Zhan

Wang

et al. 2017

Exp Ther Med

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Abstract. The aim of the present study was to assess miR-625 and Fas expression in normal and degenerative cervical cartilage endplate (CEP) tissues. Following biof-informatics analysis, the Fas gene was predicted to be one of the targets of miR-625. Quantitative PCR (qPCR) and western blotting were used to detect miR-625 and Fas expression in normal and degenerative CEP. A luciferase reporter assay was used to identify whether miR-625 could directly target the 3' untranslated region (3'-UTR) of Fas. Lentiviral overexpression and/or inhibition vectors of miR-625 (pre-miR-625)/antigomiR-625 were constructed to determine whether overexpression or inhibition of miR-625 could affect Fas and B-cell lymphoma 2 (Bcl-2) expression in cartilaginous endplate cells (CECs) and tissues. qPCR analysis demonstrated that miR-625 expression in degenerative CEP was significantly lower than in normal CEP tissue, while the production of Fas in degenerated CEP was significantly higher. Results from western blotting also showed a significant increase in Fas expression in degenerative CEP. miR-625 can bind directly to the 3'-UTR of the Fas gene. However, this inhibition was attenuated by a target mutation in the miR-625-binding site of the 3'-UTR of Fas mRNA. In addition, following transfection of CECs with pre-miR-625 and antigomiR-625, expression of Fas significantly decreased and increased, respectively, and Bcl-2 expression was upregulated and downregulated, respectively. Upregulation of miR-625 can inhibit Fas expression and further affect Bcl-2 expression in CEP degeneration, suggesting that miR-625-mediated inhibition of the Fas gene is important in cervical degeneration.

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Deregulated miR‐155 promotes Fas‐mediated apoptosis in human intervertebral disc degeneration by targeting FADD and caspase‐3

Cited by 192 publications

References 47 publications

Dysregulated miR-98 Contributes to Extracellular Matrix Degradation by Targeting IL-6/STAT3 Signaling Pathway in Human Intervertebral Disc Degeneration

Dysregulated miR-98 Contributes to Extracellular Matrix Degradation by Targeting IL-6/STAT3 Signaling Pathway in Human Intervertebral Disc Degeneration

Identification of the potential molecular targets for human intervertebral disc degeneration based on bioinformatic methods

Expression of miR-625 and Fas in cervical vertebral cartilage endplate

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