URGCP/URG4 promotes apoptotic resistance in bladder cancer cells by activating NF-κB signaling

Oncotarget. 2015 Oct 13;6(31):30887-901. doi: 10.18632/oncotarget.5134.

Abstract

Cisplatin is a well-known chemotherapeutic agent, it could cause DNA damage and induce apoptotic cell death, but the cisplatin resistance also appears, it's important to reveal the mechanisms of cisplatin resistance [1]. URGCP/URG4 is overexpressed in various tumors and plays critical role during tumor development. We found URGCP/URG4 was upregulated in bladder cancer cells and tissues, URGCP/URG4 overexpression increased the resistance to cisplatin-induced apoptosis in bladder cancer, and promoted anti-apoptotic genes expression, such as Bcl-2, Survivin, MCL-1, FLIP, and downregulated Caspase-3 expression, Knockdown of URGCP/URG4 decreased the resistance to cisplatin-induced apoptosis, and inhibited anti-apoptotic genes expression, such as Bcl-2, Survivin, MCL-1, FLIP, and upregulated Caspase-3 expression. Mechanism analysis found URGCP/URG4 activated NF-κB pathway which is a well-known anti-apoptotic pathway and promoted the expression of NF-κB targeted genes. So we speculated URGCP/URG4 regulates cisplatin-induced apoptosis by activating NF-κB pathway. We also analyzed the correlation between URGCP/URG4 expression and clinical clinicopathologic, and found its expression was positively correlated with bladder cancer progression, it can serve as a valuable prognostic factor. In summary, URGCP/URG4 promotes the resistance to cisplatin-induced apoptosis by activating NF-κB pathway, and is an unfavorable prognostic factor for bladder cancer.

Keywords: NF-κB; URGCP/URG4; apoptosis; bladder cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Blotting, Western
  • Cisplatin / pharmacology
  • Drug Resistance, Neoplasm*
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoenzyme Techniques
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neoplasm Grading
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasm Staging
  • Prognosis
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Survival Rate
  • Tumor Cells, Cultured
  • Urinary Bladder Neoplasms / drug therapy
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / mortality
  • Urinary Bladder Neoplasms / pathology*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • NF-kappa B
  • Neoplasm Proteins
  • RNA, Messenger
  • URGCP protein, human
  • Cisplatin