Upregulation of NDRG1 predicts poor outcome and facilitates disease progression by influencing the EMT process in bladder cancer

Sci Rep. 2019 Mar 26;9(1):5166. doi: 10.1038/s41598-019-41660-w.

Abstract

N-myc downstream regulated gene 1 (NDRG1) is an intracellular protein involved in cell differentiation and was recently reported to exert various effects in several cancers. However, its expression and role in bladder cancer remain unclear. Our study enrolled 100 bladder cancer patients to detect NDRG1 expression in tumour tissues by immunohistochemistry. Correlations between NDRG1 expression and clinical factors were analysed. An NDRG1 overexpression plasmid and NDRG1 siRNAs were transfected into bladder cancer cell lines. Cell biological behaviours were assessed by CCK-8, flow cytometry, wound healing and Transwell assays. Additionally, the influence of NDRG1 on epithelial-mesenchymal transition (EMT) was investigated by western blotting and real-time PCR. NDRG1 expression in urine from bladder cancer patients was examined by ELISA. NDRG1 protein levels were significantly increased in bladder cancer patients and correlated with tumour stage (p = 0.025), lymph node metastasis (p = 0.034) and overall survival (p = 0.016). Patients with high NDRG1 expression had poorer outcomes than those with low NDRG1 expression. NDRG1 overexpression was associated with increased cell proliferation, migration, and invasion and decreased apoptotic cell numbers; NDRG1 knockdown resulted in the inverse effects. Moreover, upregulated NDRG1 expression was associated with downregulated Cytokeratin 7 and Claudin-1 expression and upregulated N-cad, β-catenin and slug expression. Downregulated NDRG1 expression was associated with the inverse effects. Urine protein levels could distinguish bladder cancer patients from healthy controls, with an area under the curve of 0.909. NDRG1 promoted EMT in bladder cancer and could be an effective diagnostic and prognostic biomarker in bladder cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Case-Control Studies
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Cycle Proteins / urine
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Cell Survival / genetics
  • Disease Progression*
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / urine
  • Male
  • Middle Aged
  • Prognosis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Treatment Outcome
  • Up-Regulation / genetics*
  • Urinary Bladder Neoplasms / diagnosis
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / urine

Substances

  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • N-myc downstream-regulated gene 1 protein
  • RNA, Messenger