HIF-1α promotes ZEB1 expression and EMT in a human bladder cancer lung metastasis animal model

Jianning Zhu, Zhixin Huang, Mengzhao Zhang, Weiyi Wang, Hua Liang, Jin Zeng, Kaijie Wu, Xinyang Wang, Jer Tsong Hsieh, Peng Guo, Jinhai Fan

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Lung is one of the most common sites for bladder cancer to metastasize. Although the involvement of the epithelial-to-mesenchymal transition (EMT) in bladder cancer progression has been established, the mechanism of EMT induction remains unclear. In order to investigate this, T24-parental (P) and T24-lung (L) bladder cancer cells were obtained from primary tumors and lung metastatic sites of an animal model with orthotopic spontaneous metastatic bladder cancer, according to a protocol previously described. Compared with T24-P cells, mesenchymal-like T24-L cells exhibited an increased ability in tumor invasion and metastasis, as well as an increased expression of hypoxia-inducible factor (HIF)-1α, zinc finger E-box-binding homeobox 1 (ZEB1), vimentin and N-cadherin and lower level of cytokeratin 18 were observed. Mechanistically, it was identified that HIF-1α increases ZEB1 expression and subsequently regulates the expression of EMT-related genes in both HIF-1α knocking down by siRNA and gain-in HIF-1α by hypoxia culture cell models. In addition, the expression of HIF-1α and ZEB1 in bladder cancer tissues were increased compared with normal bladder epithelial tissues, as well as significantly increased in the high-grade, invasive and metastatic bladder cancer tissues compared with low-grade, superficial and non-metastatic bladder cancer tissues by using immune-histochemical staining assay. Notably, the protein level of HIF-1α was positively associated with that of ZEB1 in bladder cancer tissues. Results from the present study indicate that HIF-1α promotes ZEB1 expression and EMT in the T24-L human bladder cancer lung metastasis animal model, suggesting that HIF-1α serves an important function in the metastasis of bladder cancer, and HIF-1α and ZEB1 may be potential targets for inhibiting bladder metastasis in the future.

Original languageEnglish (US)
Pages (from-to)3482-3489
Number of pages8
JournalOncology Letters
Volume15
Issue number3
DOIs
StatePublished - Mar 1 2018

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Keywords

  • Bladder cancer
  • Epithelial-to-mesenchymal transition
  • Metastasis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zhu, J., Huang, Z., Zhang, M., Wang, W., Liang, H., Zeng, J., Wu, K., Wang, X., Hsieh, J. T., Guo, P., & Fan, J. (2018). HIF-1α promotes ZEB1 expression and EMT in a human bladder cancer lung metastasis animal model. Oncology Letters, 15(3), 3482-3489. https://doi.org/10.3892/ol.2018.7764