NELL2 modulates cell proliferation and apoptosis via ERK pathway in the development of benign prostatic hyperplasia

Abstract

Benign prostatic hyperplasia (BPH) is a quite common illness but its etiology and mechanism remain unclear. Neural epidermal growth factor-like like 2 (NELL2) plays multifunctional roles in neural cell growth and is strongly linked to the urinary tract disease. Current study aims to determine the expression, functional activities and underlying mechanism of NELL2 in BPH. Human prostate cell lines and tissues from normal human and BPH patients were utilized. Immunohistochemical staining, immunofluorescent staining, RT-PCR and Western-blotting were performed. We further generated cell models with NELL2 silenced or overexpressed. Subsequently, proliferation, cycle, and apoptosis of prostate cells were determined by CCK-8 assay and flow cytometry analysis. The epithelial-mesenchymal transition (EMT) and fibrosis process were also analyzed. Our study revealed that NELL2 was upregulated in BPH samples and localized in the stroma and the epithelium compartments of human prostate tissues. NELL2 deficiency induced a mitochondrial-dependent cell apoptosis, and inhibited cell proliferation via phosphorylating ERK1/2 activation. Additionally, suppression of ERK1/2 with U0126 incubation could significantly reverse NELL2 deficiency triggered cell apoptosis. Consistently, overexpression of NELL2 promoted cell proliferation and inhibited cell apoptosis. However, NELL2 interference was observed no effect on EMT and fibrosis process. Our novel data demonstrated that upregulation of NELL2 in the enlarged prostate could contribute to the development of BPH through enhancing cell proliferation and inhibited a mitochondrial-dependent cell apoptosis via the ERK pathway. The NELL2-ERK system might represent an important target to facilitate the development of future therapeutic approaches in BPH.

Neural Epidermal Growth Factor-Like Like Protein 2 Is Expressed in Human Oligodendroglial Cell Types

“…A particularly high expression of NELL2 was detected in NSCs that were apically located within the neural rosettes compared to cells positioned close to the basal level, and this was confirmed by confocal imaging of human neural rosettes double labelled with NelL2 and ZO1 antibodies ( Figure 3E ). These data are consistent with previous studies in human cell lines and rats that indicated Nell2 modulates cell proliferation and growth ( Kim et al, 2020 ; Liu et al, 2021 ). Since human iPSC-derived cortical brain organoids contain both mature neurons and glia, we next analyzed the expression of NELL2 in these cell types in 8- and 10-week-old brain organoids by co-staining with NEUN for neurons, GFAP for astrocytes, and CNPase for oligodendrocytes.…”

“…Our confocal 3D reconstruction imaging of the human rosettes strongly suggests Nell2 is intracellular (Figure 3E). Collectively, these data suggest that NELL2 may regulate the proliferation of rNSCs during development, in line with previous studies (Aihara et al, 2003;Nelson et al, 2004;Jeong et al, 2008) that demonstrated that NELL2 modulates cell proliferation and growth in human and rat cells (Kim et al, 2020;Liu et al, 2021). We certainly detected consistent differences in expression levels between rNSC and cNSC populations.…”

Transcriptional Regulatory Role of NELL2 in Preproenkephalin Gene Expression

“…As expected, PMA treatment stimulated PPE-Luc, while co-transfection of either NELL2 expression vectors or NELL2 expression vectors + BFA inhibited PMA-induced PPE-Luc activity. Given that NELL2 is known to be related to ERK activation ( Aihara et al, 2003 ; Choi et al, 2010 ; Kim et al, 2014 ; 2015 ; Liu et al, 2021 ), one of the multiple downstream pathways of PKC signaling, we next examined the involvement of ER-localized NELL2 in the activity of ERK, as represented by level of phosphorylated ERK (pERK). In western blot analyses, pERK was undetectable in control NIH3T3 cells, but was induced strongly by PMA treatment ( Fig.…”

Upregulation of Metallothionein 1 G (MT1G) Negatively Regulates Ferroptosis in Clear Cell Renal Cell Carcinoma by Reducing Glutathione Consumption

“…For cell apoptosis analysis, a FITC Annexin V Apoptosis Detection Kit I (BD Biosciences, USA) was used. BPH-1, WPMY-1, and RWPE-1 cells (1 × 10 6 cells) were harvested and then stained with the FITC Annexin V Apoptosis Detection Kit I reagents according to the manufacturer's instructions [ 21 ].…”