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

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

doi:10.3892/ol.2018.9155

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

Authors:
- Li Zhao
- Tao Zhang
- Hao Geng
- Zhi‑Qi Liu
- Zhao‑Feng Liang
- Zhi‑Qiang Zhang
- Jie Min
- De‑Xin Yu
- Cai‑Yun Zhong
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Affiliations: Department of Urology, Affiliated Fuyang Hospital of Anhui Medical University, Fuyang, Anhui 236000, P.R. China, Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230032, P.R. China, Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
Published online on: July 17, 2018 https://doi.org/10.3892/ol.2018.9155
Pages: 4628-4634

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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.

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