title: MiR-138-5p promotes TNF-α-induced apoptosis in human intervertebral disc degeneration by targeting SIRT1 through PTEN/PI3K/Akt signaling.
abstract: The role of apoptosis in the pathogenesis of intervertebral disc degeneration (IDD) remains enigmatic. Accumulating evidence has shown that the apoptotic machinery is regulated by miRNAs. The aim of this study was to evaluate the effect of miR-138-5p on apoptosis in human NP cells induced by TNF-α and to explore the mechanism of this process. The expression of miR-138-5p was determined in nucleus pulposus (NP) tissues from patients with IDD and controls using RT-qPCR, and we showed that miR-138-5p was significantly upregulated in degenerative NP tissues. Additionally, TNF-α-induced apoptosis was inhibited when using a miR-138-5p inhibitor in human NP cells, and silencing of miR-138-5p dramatically suppressed the expression of cleaved caspase-3. Moreover, bioinformatics target prediction identified SIRT1 as a putative target of miR-138-5p. Knockdown of miR-138-5p was shown to upregulate SIRT1 expression by direct targeting its 3'-UTR, an effect that was abolished by mutation of the miR-138-5p binding sites. Furthermore, inhibition of miR-138-5p downregulated PTEN protein expression and promoted activation of PI3K/AKT, and knockdown of either SIRT1 or the PI3K/Akt inhibitor (LY294002) abolished the effect of miR-138-5p on NP cell apoptosis. Together, these results indicate that miR-138-5p is a novel regulator of human NP cell apoptosis induced by TNF-α. The knockout of miR-138-5p expression protected human NP cells from apoptosis via the upregulation of SIRT1, which was possibly mediated via PTEN/PI3K/Akt signaling. These findings suggest that the miR-138-5p/SIRT1/PTEN/PI3K/Akt signaling pathway might represent a novel therapeutic target for the prevention of IDD.
authors.affiliation: Department of Pediatric Orthopedics, Honghui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, Xi'an 710054, PR China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Spinal Surgery Department, Honghui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, Xi'an 710054, PR China.
authors.forename: Dongqi
authors.initials: D
authors.lastname: Wang
authors.affiliation: Radiology Department, XD Group Hospital, Shaanxi, Xi'an 710077, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yan
authors.affiliation: Radioactive Interventional Division, Honghui Hospital, Xi'an Jiaotong University College of Medicine, Shaanxi, Xi'an 710054, PR China. Electronic address: huijunyuanhh@163.com.
authors.forename: Huijun
authors.initials: H
authors.lastname: Yuan
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001483:Base Sequence; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D055959:Intervertebral Disc Degeneration / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000070614:Nucleus Pulposus / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D056564:Sirtuin 1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; C546110:MIRN138 microRNA, human; D035683:MicroRNAs; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D056564:Sirtuin 1
keywords: Apoptosis; Intervertebral disc degeneration (IDD); MiR-138-5p; Nucleus pulposus (NP); SIRT1/PTEN/PI3K/Akt