Effect of microRNA-21 on the proliferation of human degenerated nucleus pulposus by targeting programmed cell death 4

Abstract

This study aims to explore the effect of microRNA-21 (miR-21) on the proliferation of human degenerated nucleus pulposus (NP) by targeting programmed cell death 4 (PDCD4) tumor suppressor. NP tissues were collected from 20 intervertebral disc degeneration (IDD) patients, and from 5 patients with traumatic spine fracture. MiR-21 expressions were tested. NP cells from IDD patients were collected and divided into blank control group, negative control group (transfected with miR-21 negative sequences), miR-21 inhibitor group (transfected with miR-21 inhibitors), miR-21 mimics group (transfected with miR-21 mimics) and PDCD4 siRNA group (transfected with PDCD4 siRNAs). Cell growth was estimated by Cell Counting Kit-8; PDCD4, MMP-2,MMP-9 mRNA expressions were evaluated by qRT-PCR; PDCD4, c-Jun and p-c-Jun expressions were tested using western blot. In IDD patients, the expressions of miR-21 and PDCD4 mRNA were respectively elevated and decreased (both P<0.05). The miR-21 expressions were positively correlated with Pfirrmann grades, but negatively correlated with PDCD4 mRNA (both P<0.001). In miR-21 inhibitor group, cell growth, MMP-2 and MMP-9 mRNA expressions, and p-c-Jun protein expressions were significantly lower, while PDCD4 mRNA and protein expressions were higher than the other groups (all P<0.05). These expressions in the PDCD4 siRNA and miR-21 mimics groups was inverted compared to that in the miR-21 inhibitor group (all P<0.05). MiR-21 could promote the proliferation of human degenerated NP cells by targeting PDCD4, increasing phosphorylation of c-Jun protein, and activating AP-1-dependent transcription of MMPs, indicating that miR-21 may be a crucial biomarker in the pathogenesis of IDD.

Evaluation of miRNA-196a2 and apoptosis-related target genes: ANXA1, DFFA and PDCD4 expression in gastrointestinal cancer patients: A pilot study

“…Diminished PDCD4 expression was previously reported in head and neck squamous cell carcinoma [ 80 ], lung cancer [ 81 ], bladder cancer [ 82 ], and colon adenocarcinoma [ 83 ] compared to normal tissues. PDCD4 is involved in cell apoptosis, neoplastic transformation, and tumor progression [ 84 , 85 ]. PDCD4 exerts its function by binding to the eukaryotic translation initiation factor 4A1 and hindering mRNA translation initiation and capping [ 86 ].…”

“…PDCD4 exerts its function by binding to the eukaryotic translation initiation factor 4A1 and hindering mRNA translation initiation and capping [ 86 ]. PDCD4 could also influence different cellular transcriptional pathways in various tumors [ 85 ]. PDCD4 suppressed carbonic anhydrase II (CAII) in human embryonic kidney [ 87 ], delayed cell cycle transition from G1 to S phase in glioma cancer cell [ 88 ], inhibited colon cancer cell invasion through suppressing MAP4K1 [ 89 ], and phosphorylated the specificity protein transcription factors in colorectal cells [ 90 ], thus promoting essential events important in driving invasion and metastasis [ 82 ].…”

“…Similar effects have also been reported in studies conducted in colon and HCC cells [ 89 , 94 , 95 ]. In addition, it was found to be preferentially expressed in tumor promotor-resistant cells and suppressed in promotion-sensitive cells undergoing neoplastic transformation [ 85 ].…”

The PI3K/Akt pathway: a critical player in intervertebral disc degeneration

“…Interestingly, transfection of human NP cells with miR-21 mimic dramatically increased Akt activity via targeting PTEN, leading to upregulation of cyclin D1 expression and subsequent cell proliferation [ 95 ]. It is worth noting that overexpression of miR-21 could also stimulate these cell proliferation via silencing of programmed cell death 4 (PDCD4) [ 96 ]. Recently, Li et al identified growth arrest specific gene 1 (GAS1) as a direct and functional target of miR-184 [ 97 ].…”

microRNA-96 regulates the proliferation of nucleus pulposus cells by targeting ARID2/AKT signaling

“…In addition, a number of studies have demonstrated that dysregulated miRNAs participate in various human cancers and act as oncogenes or suppressor genes, depending the function of their targets (16,17). Additionally, several miRNAs were reported to regulate various target genes, pathways and processes essential for the pathogenesis of IDD (18)(19)(20). However, although miRNAs have been investigated extensively in recent years, their roles in IDD development, and as potential markers for microRNA-96 regulates the proliferation of nucleus pulposus cells by targeting ARID2/AKT signaling diagnosis and prognosis, remain unclear.…”