MAPK/AP‑1 pathway regulates benzidine‑induced cell proliferation through the control of cell cycle in human normal bladder epithelial cells

Li Zhao, Tao Zhang, Hao Geng, Zhi Qi Liu, Zhao Feng Liang, Zhi Qiang Zhang, Jie Min, De Xin Yu, Cai Yun Zhong

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Bladder cancer is the most common malignancy of the urinary tract. Long-term exposure to benzidine is one of the major causes of bladder cancer. However, the mechanism of benzidine‑induced bladder cancer is not yet sufficiently characterized. Dysregulated cell proliferation serves a critical role in cancer initiation and development; whether benzidine promotes cell proliferation, and the role of MAPKs in this process, have not previously been investigated. The present study aimed to investigate the benzidine-induced modulation of intracellular mitogen-activated protein kinases (MAPKs) and activator protein-1 (AP-1) signaling cascades on cell proliferation in SV-40 immortalized human uroepithelial cells (SV‑HUC‑1). It was identified that benzidine exposure enhanced the proliferation of SV-HUC-1 cells, promoted the transition of cells from G1 to S phase and altered the expression level of cell cycle-associated genes at the mRNA and protein levels. Furthermore, exposure of the SV-HUC-1 cells to benzidine was associated with the activation of MAPKs, including extracellular regulated protein kinases 1 and 2, p38 and Jun N-terminal kinase. The downstream target of MAPKs, AP-1 monomers, was also activated. Benzidine-induced proliferation was reversed by MAPK‑specific inhibitors. Thus, the present study demonstrated that benzidine enhances the proliferation of bladder cells via activating the MAPK/AP-1 pathway, which may provide novel insights into the molecular mechanisms of benzidine-initiated bladder tumorigenesis, as well as cancer prevention.

Original languageEnglish
Pages (from-to)4628-4634
Number of pages7
JournalOncology Letters
Volume16
Issue number4
DOIs
StatePublished - Oct 2018
Externally publishedYes

Keywords

  • Benzidine
  • Bladder cancer
  • Cell proliferation
  • Mitogen activated protein kinase/activator protein-1
  • SV-HUC-1 cells

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