NELL2 Modulates Cell Proliferation and Apoptosis via ERK Pathway in the Development of Benign Prostatic Hyperplasia.

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.

[1]  Shuntai Chen,et al.  IGF-1R inhibition induces MEK phosphorylation to promote survival in colon carcinomas , 2020, Signal Transduction and Targeted Therapy.

[2]  R. Dhir,et al.  Tight junction protein claudin‐1 is downregulated by TGF‐β1 via MEK signaling in benign prostatic epithelial cells , 2020, The Prostate.

[3]  Eun Jin Seo,et al.  NELL2 Function in Axon Development of Hippocampal Neurons , 2020, Molecules and cells.

[4]  M. Matzuk,et al.  NELL2-mediated lumicrine signaling through OVCH2 is required for male fertility , 2020, Science.

[5]  Xinghuan Wang,et al.  Identification and functional activity of matrix-remodeling associated 5 (MXRA5) in benign hyperplastic prostate , 2020, Aging.

[6]  Prakash Kulkarni,et al.  Stromal‐epithelial interactions in prostate cancer: Overexpression of PAGE4 in stromal cells inhibits the invasive ability of epithelial cells , 2020, Journal of cellular biochemistry.

[7]  X. Tan,et al.  Dysregulated Tgfbr2/ERK-Smad4/SOX2 signaling promotes lung squamous cell carcinoma formation. , 2019, Cancer research.

[8]  Chao Li,et al.  Resveratrol induces apoptosis of benign prostatic hyperplasia epithelial cell line (BPH-1) through p38 MAPK-FOXO3a pathway , 2019, BMC Complementary and Alternative Medicine.

[9]  R. Seger,et al.  Nuclear ERK: Mechanism of Translocation, Substrates, and Role in Cancer , 2019, International journal of molecular sciences.

[10]  Xinghuan Wang,et al.  Upregulated Interleukin 21 Receptor Enhances Proliferation and Epithelial-Mesenchymal Transition Process in Benign Prostatic Hyperplasia , 2019, Front. Endocrinol..

[11]  Jialu Zhang,et al.  Stomatin‐like protein 2 inhibits cisplatin‐induced apoptosis through MEK/ERK signaling and the mitochondrial apoptosis pathway in cervical cancer cells , 2018, Cancer science.

[12]  Zhiguang Qiao,et al.  Oxytocin: its role in benign prostatic hyperplasia via the ERK pathway. , 2017, Clinical science.

[13]  B. Lee,et al.  A Role of Central NELL2 in the Regulation of Feeding Behavior in Rats , 2017, Molecules and cells.

[14]  Zhongjun Liu,et al.  Regulation of Intrinsic and Extrinsic Apoptotic Pathways in Osteosarcoma Cells Following Oleandrin Treatment , 2016, International journal of molecular sciences.

[15]  W. Xue,et al.  Regulation of Prostate Development and Benign Prostatic Hyperplasia by Autocrine Cholinergic Signaling via Maintaining the Epithelial Progenitor Cells in Proliferating Status , 2016, Stem cell reports.

[16]  G. Morgia,et al.  Endocrine control of benign prostatic hyperplasia , 2016, Andrology.

[17]  G. Andriole,et al.  Management of Benign Prostatic Hyperplasia. , 2016, Annual review of medicine.

[18]  M. Oelke,et al.  EAU Guidelines on the Assessment of Non-neurogenic Male Lower Urinary Tract Symptoms including Benign Prostatic Obstruction. , 2015, European urology.

[19]  P. Xie,et al.  iTRAQ-based quantitative proteomic analysis of cerebrospinal fluid reveals NELL2 as a potential diagnostic biomarker of tuberculous meningitis. , 2015, International journal of molecular medicine.

[20]  R. Kirby,et al.  Burden of male lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) – focus on the UK , 2015, BJU international.

[21]  Ritsuko Nakamura,et al.  Expression and regulatory effects on cancer cell behavior of NELL1 and NELL2 in human renal cell carcinoma , 2015, Cancer science.

[22]  E. Choi,et al.  Compromised MAPK signaling in human diseases: an update , 2015, Archives of Toxicology.

[23]  K. Eliceiri,et al.  Characterization of Fibrillar Collagens and Extracellular Matrix of Glandular Benign Prostatic Hyperplasia Nodules , 2014, PloS one.

[24]  E. J. Choi,et al.  Neural Epidermal Growth Factor-Like Like Protein 2 (NELL2) Promotes Aggregation of Embryonic Carcinoma P19 Cells by Inducing N-Cadherin Expression , 2014, PloS one.

[25]  J. Macoska,et al.  Prostatic fibrosis, lower urinary tract symptoms, and BPH , 2013, Nature Reviews Urology.

[26]  Dong Hee Kim,et al.  The E2F1 oncogene transcriptionally regulates NELL2 in cancer cells. , 2013, DNA and cell biology.

[27]  A. Salonia,et al.  Periurethral fibrosis secondary to prostatic inflammation causing lower urinary tract symptoms: a prospective cohort study. , 2013, Urology.

[28]  J. Hollingsworth,et al.  Prostatic fibrosis is associated with lower urinary tract symptoms. , 2012, The Journal of urology.

[29]  J. Caprioli,et al.  The Neuronal EGF-Related Gene Nell2 Interacts with Macf1 and Supports Survival of Retinal Ganglion Cells after Optic Nerve Injury , 2012, PloS one.

[30]  B. Lee,et al.  Regulation of the female rat estrous cycle by a neural cell-specific epidermal growth factor-like repeat domain containing protein, NELL2 , 2011, Molecules and cells.

[31]  E. J. Choi,et al.  Estrogen-dependent Transcription of the NEL-like 2 (NELL2) Gene and Its Role in Protection from Cell Death* , 2010, The Journal of Biological Chemistry.

[32]  J. Chambard,et al.  ERK and cell death: Mechanisms of ERK‐induced cell death – apoptosis, autophagy and senescence , 2010, The FEBS journal.

[33]  B. Lee,et al.  Region- and neuronal phenotype-specific expression of NELL2 in the adult rat brain. , 2008, Molecules and cells.

[34]  J. Pouysségur,et al.  The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition , 2007, Oncogene.

[35]  M. Berger,et al.  Convection-enhanced delivery of Ls-TPT enables an effective, continuous, low-dose chemotherapy against malignant glioma xenograft model. , 2006, Neuro-oncology.

[36]  John T. Wei,et al.  The economics of benign prostatic hyperplasia and lower urinary tract symptoms in the united states , 2006, Current urology reports.

[37]  Hong Zhong,et al.  Novel Blood Biomarkers of Human Urinary Bladder Cancer , 2006, Clinical Cancer Research.

[38]  S. Nair,et al.  ERK and JNK signaling pathways are involved in the regulation of activator protein 1 and cell death elicited by three isothiocyanates in human prostate cancer PC-3 cells. , 2006, Carcinogenesis.

[39]  Li‐jun Wu,et al.  Phosphorylated extracellular signal-regulated kinase up-regulated p53 expression in shikonin-induced HeLa cell apoptosis. , 2005, Chinese medical journal.

[40]  R. Craig,et al.  MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol , 2004, Oncogene.

[41]  B. Nelson,et al.  NELL2 promotes motor and sensory neuron differentiation and stimulates mitogenesis in DRG in vivo. , 2004, Developmental biology.

[42]  Jun Luo,et al.  Decreased gene expression of steroid 5 alpha‐reductase 2 in human prostate cancer: Implications for finasteride therapy of prostate carcinoma , 2003, The Prostate.

[43]  K. Tanizawa,et al.  A neuron-specific EGF family protein, NELL2, promotes survival of neurons through mitogen-activated protein kinases. , 2003, Brain research. Molecular brain research.

[44]  L. Greene,et al.  Nerve Growth Factor (NGF) Down-regulates the Bcl-2 Homology 3 (BH3) Domain-only Protein Bim and Suppresses Its Proapoptotic Activity by Phosphorylation* , 2002, The Journal of Biological Chemistry.

[45]  C. Ha,et al.  Ontogeny and the possible function of a novel epidermal growth factor‐like repeat domain‐containing protein, NELL2, in the rat brain , 2002, Journal of neurochemistry.

[46]  F. Porteu,et al.  IEX‐1: a new ERK substrate involved in both ERK survival activity and ERK activation , 2002, The EMBO journal.

[47]  H. Schägger.  Respiratory chain supercomplexes of mitochondria and bacteria. , 2002, Biochimica et biophysica acta.

[48]  M Hareyama,et al.  MEK/ERK pathway protects ionizing radiation-induced loss of mitochondrial membrane potential and cell death in lymphocytic leukemia cells , 2002, Cell Death and Differentiation.

[49]  A. Borkhardt,et al.  Ras-mediated activation of ERK by cisplatin induces cell death independently of p53 in osteosarcoma and neuroblastoma cell lines , 2002, Cancer Chemotherapy and Pharmacology.

[50]  J. Trent,et al.  Gene expression signature of benign prostatic hyperplasia revealed by cDNA microarray analysis , 2002, The Prostate.

[51]  T. Mak,et al.  ERK Activation Mediates Cell Cycle Arrest and Apoptosis after DNA Damage Independently of p53* , 2002, The Journal of Biological Chemistry.

[52]  Huitu Liu,et al.  MAPK signal pathways in the regulation of cell proliferation in mammalian cells , 2002, Cell Research.

[53]  I. Pastan,et al.  PAGE4 is a cytoplasmic protein that is expressed in normal prostate and in prostate cancers. , 2002, Molecular cancer therapeutics.

[54]  Hung-Yun Lin,et al.  Resveratrol induces apoptosis in thyroid cancer cell lines via a MAPK- and p53-dependent mechanism. , 2002, The Journal of clinical endocrinology and metabolism.

[55]  S. Kuroda,et al.  Brain specific human genes, NELL1 and NELL2, are predominantly expressed in neuroblastoma and other embryonal neuroepithelial tumors. , 2001, Neurologia medico-chirurgica.

[56]  P. Fisher,et al.  Deoxycholic acid (DCA) causes ligand-independent activation of epidermal growth factor receptor (EGFR) and FAS receptor in primary hepatocytes: inhibition of EGFR/mitogen-activated protein kinase-signaling module enhances DCA-induced apoptosis. , 2001, Molecular biology of the cell.

[57]  A. Papatsoris,et al.  Molecular 'palpation' of BPH: a tale of MAPK signalling? , 2001, Trends in molecular medicine.

[58]  S. E. F. Tran,et al.  MAPK/ERK Overrides the Apoptotic Signaling from Fas, TNF, and TRAIL Receptors* , 2001, The Journal of Biological Chemistry.

[59]  A. Dilella,et al.  Identification of Genes Differentially Expressed in Benign Prostatic Hyperplasia , 2001, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[60]  R. Lefkowitz,et al.  New mechanisms in heptahelical receptor signaling to mitogen activated protein kinase cascades , 2001, Oncogene.

[61]  M. Fujimiya,et al.  Immunocytochemical localization of a neuron-specific thrombospondin-1-like protein, NELL2: light and electron microscopic studies in the rat brain. , 2000, Brain research. Molecular brain research.

[62]  T. Abe,et al.  Biochemical characterization and expression analysis of neural thrombospondin-1-like proteins NELL1 and NELL2. , 1999, Biochemical and biophysical research communications.

[63]  Helmut Klocker,et al.  Rapid signalling by androgen receptor in prostate cancer cells , 1999, Oncogene.

[64]  G. Kramer,et al.  Elastin gene expression in benign prostatic hyperplasia , 1999, The Prostate.

[65]  F. Hobbs,et al.  Identification of a Novel Inhibitor of Mitogen-activated Protein Kinase Kinase* , 1998, The Journal of Biological Chemistry.

[66]  Y. Ip,et al.  Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development. , 1998, Current opinion in cell biology.

[67]  T. Katagiri,et al.  Cloning and characterization of two novel human cDNAs (NELL1 and NELL2) encoding proteins with six EGF-like repeats. , 1996, Genomics.

[68]  Xiaodong Wang,et al.  Induction of Apoptotic Program in Cell-Free Extracts: Requirement for dATP and Cytochrome c , 1996, Cell.

[69]  P. Handford,et al.  The structure of a Ca2+-binding epidermal growth factor-like domain: Its role in protein-protein interactions , 1995, Cell.

[70]  K. Hori,et al.  New gene, nel, encoding a Mr 93 K protein with EGF‐like repeats is strongly expressed in neural tissues of early stage chick embryos , 1995, Developmental dynamics : an official publication of the American Association of Anatomists.

[71]  P. Walsh,et al.  The development of human benign prostatic hyperplasia with age. , 1984, The Journal of urology.

[72]  D. Kardamakis,et al.  Increased Bax/Bcl-2 ratio up-regulates caspase-3 and increases apoptosis in the thymus of patients with myasthenia gravis. , 2007, In vivo.

[73]  R. Getzenberg,et al.  Fingerprinting the diseased prostate: Associations between BPH and prostate cancer , 2004, Journal of cellular biochemistry.

[74]  Li Sheng-mei,et al.  On the Structure of "秀才秀才,错字布袋 , 2003 .

[75]  R. Davis,et al.  Signal transduction by the c-Jun N-terminal kinase. , 1999, Biochemical Society symposium.

[76]  G. Kramer,et al.  Phenotypic characterization of infiltrating leukocytes in benign prostatic hyperplasia. , 1992, Laboratory investigation; a journal of technical methods and pathology.