Suppression of progranulin expression inhibits bladder cancer growth and sensitizes cancer cells to cisplatin

Oncotarget. 2016 Jun 28;7(26):39980-39995. doi: 10.18632/oncotarget.9556.

Abstract

We have recently demonstrated a critical role for progranulin in bladder cancer. Progranulin contributes, as an autocrine growth factor, to the transformed phenotype by modulating Akt-and MAPK-driven motility, invasion and anchorage-independent growth. Progranulin also induces F-actin remodeling by interacting with the F-actin binding protein drebrin. In addition, progranulin is overexpressed in invasive bladder cancer compared to normal tissue controls, suggesting that progranulin might play a key role in driving the transition to the invasive phenotype of urothelial cancer. However, it is not established whether targeting progranulin could have therapeutic effects on bladder cancer. In this study, we stably depleted urothelial cancer cells of endogenous progranulin by shRNA approaches and determined that progranulin depletion severely inhibited the ability of tumorigenic urothelial cancer cells to migrate, invade and grow in anchorage-independency. We further demonstrate that progranulin expression is critical for tumor growth in vivo, in both xenograft and orthotopic tumor models. Notably, progranulin levels correlated with response to cisplatin treatment and were upregulated in bladder tumors. Our data indicate that progranulin may constitute a novel target for therapeutic intervention in bladder tumors. In addition, progranulin may serve as a novel biomarker for bladder cancer.

Keywords: anchorage-independent growth; bladder cancer; motility; progranulin; tumor formation in vivo.

MeSH terms

  • Actins / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Biomarkers, Tumor
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Cisplatin / pharmacology*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Signaling System
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • Phenotype
  • Progranulins
  • RNA, Small Interfering / metabolism
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / metabolism*
  • Urothelium / pathology

Substances

  • Actins
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • Progranulins
  • RNA, Small Interfering
  • Cisplatin