Possible correlation of sonic hedgehog signaling with epithelial–mesenchymal transition in muscle-invasive bladder cancer progression

Koichi Kitagawa, Katsumi Shigemura, Shian Ying Sung, Kuan Chou Chen, Chao Ching Huang, Yi Te Chiang, Ming Che Liu, Tzu Wen Huang, Fukashi Yamamichi, Toshiro Shirakawa, Masato Fujisawa

研究成果: Article

2 引文 斯高帕斯(Scopus)

摘要

Purpose: To investigate the role of sonic hedgehog (Shh) signaling and epithelial–mesenchymal transition (EMT) in bladder cancer progression and invasion. Methods: We cultured three bladder cancer cell lines, muscle-invasive T24 and 5637, and non-muscle-invasive KK47, in the presence of a recombinant-Shh (r-Shh) protein or cyclopamine, a Shh signaling inhibitor, to investigate proliferation and expression of EMT markers. Wound-healing assays and transwell assay were performed to evaluate cell invasion and migration. Mice were then inoculated with bladder cancer cells and treated with cyclopamine. Mouse tumor samples were stained for Shh signaling and EMT markers. Results: R-Shh protein enhanced cell proliferation, whereas cyclopamine significantly suppressed cell proliferation, especially in invasive cancer (5637 and T24) (p < 0.05). R-Shh protein promoted EMT, suppressed E-cadherin and enhanced N-cadherin and vimentin and Gli1, an Shh downstream molecule, while cyclopamine blocked EMT, especially in 5637 and T24. Cyclopamine also inhibited cell invasion and migration in vitro. In the animal study, intraperitoneal injection of cyclopamine significantly suppressed tumor growth in 5637 and T24 in mice (p = 0.01 and p = 0.004, respectively) and slightly suppressing KK47 tumor growth (p = 0.298). Significant cyclopamine-induced suppression of Gli1 in 5637 and T24 mouse tumors (both p = 0.03) was seen, suggesting that muscle-invasive bladder cancer may be more dependent on Shh signaling than non-muscle-invasive bladder cancer. Conclusions: Shh signaling and EMT were especially enhanced in muscle-invasive bladder cancer progression and invasion, and suppressed by the inhibition of Shh signaling.

原文English
頁(從 - 到)2261-2271
頁數11
期刊Journal of Cancer Research and Clinical Oncology
145
發行號9
DOIs
出版狀態Published - 2019 九月 4

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Kitagawa, K., Shigemura, K., Sung, S. Y., Chen, K. C., Huang, C. C., Chiang, Y. T., Liu, M. C., Huang, T. W., Yamamichi, F., Shirakawa, T., & Fujisawa, M. (2019). Possible correlation of sonic hedgehog signaling with epithelial–mesenchymal transition in muscle-invasive bladder cancer progression. Journal of Cancer Research and Clinical Oncology, 145(9), 2261-2271. https://doi.org/10.1007/s00432-019-02987-z