Derlin-1 overexpression confers poor prognosis in muscle invasive bladder cancer and contributes to chemoresistance and invasion through PI3K/AKT and ERK/MMP signaling

Oncotarget. 2017 Mar 7;8(10):17059-17069. doi: 10.18632/oncotarget.15001.


Derlin-1 has been found to be overexpressed in several human cancers. However, its clinical significance and biological roles in bladder cancer remain unexplored. Here, we found that Derlin-1 was upregulated in 38.6% (58/150) cases of cancer samples. The rate of Derlin-1 overexpression was higher in muscle invasive bladder cancer (MIBC) than non-muscle invasive bladder cancer (NMIBC) (p=0.0079). Derlin-1 was a predicting factor for poor patient prognosis. Derlin-1 depletion inhibited while its overexpression facilitated cell invasion and colony formation. In addition, Derlin-1 overexpression induced cisplatin resistance while its depletion sensitized cancer cells to cisplatin. Further analysis demonstrated that Derlin-1 activated AKT phosphorylation and upregulated Bcl-2 expression. Blockage of AKT signaling by LY294005 abolished the effects of Derlin-1 on Bcl-2 and cisplatin resistance. Immunoprecipitation indicated Derlin-1 interacted with p110α subunit of PI3K. In addition, we showed that Derlin-1 depletion downregulated and its overexpression upregulated cell MMP-2/9 expression and ERK phosphorylation. Derlin-1 mediated upregulation of MMP-2/9 could be blocked by ERK inhibitor. In conclusion, our study demonstrated that Derlin-1 is overexpressed in bladder cancer and promotes malignant phenotype through ERK/MMP and PI3K/AKT/Bcl-2 signaling pathway.

Keywords: AKT; Derlin-1; ERK; bladder cancer; prognosis.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Blotting, Western
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • MAP Kinase Signaling System
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinases / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Middle Aged
  • Muscles / metabolism
  • Muscles / pathology
  • Neoplasm Invasiveness
  • Phosphorylation
  • Prognosis
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA Interference
  • Signal Transduction
  • Urinary Bladder Neoplasms / drug therapy
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / metabolism*


  • Antineoplastic Agents
  • DERL1 protein, human
  • Membrane Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Class Ia Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • Matrix Metalloproteinases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Cisplatin