Cisplatin-Induced Sonic Hedgehog Signaling Mediates Epithelial-Mesenchymal Transition in Hertwig’s Epithelial Root Sheath Cells

  • Ishii Hanako
    Section of Pediatric, Department of Oral Growth and Development, Fukuoka Dental College Oral Medicine Research Center, Fukuoka Dental College
  • Yoshida Mizuki
    Oral Medicine Research Center, Fukuoka Dental College Section of Geriatric Dentistry, Department of General Dentistry, Fukuoka Dental College
  • Kajiya Hiroshi
    Oral Medicine Research Center, Fukuoka Dental College Section of Cellular Physiology, Department of Physiological Science and Molecular Biology, Fukuoka Dental College
  • Matsuo Satoru
    Section of Pediatric, Department of Oral Growth and Development, Fukuoka Dental College
  • Toda-Nakamura Masako
    Section of Pediatric, Department of Oral Growth and Development, Fukuoka Dental College
  • Mori-Yamamoto Nana
    Oral Medicine Research Center, Fukuoka Dental College Section of Periodontology, Department of Odontology, Fukuoka Dental College
  • Fujisaki Seiichi
    Oral Medicine Research Center, Fukuoka Dental College Section of Oral Implantology, Department of Oral Rehabilitation, Fukuoka Dental College
  • Oka Kyoko
    Section of Pediatric, Department of Oral Growth and Development, Fukuoka Dental College
  • Ozaki Masao
    Section of Pediatric, Department of Oral Growth and Development, Fukuoka Dental College
  • Ohno Jun
    Oral Medicine Research Center, Fukuoka Dental College

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<p>In this study, we determined whether cisplatin can induce epithelial-mesenchymal transition (EMT) via the activation of Sonic hedgehog (Shh) or glioma-associated antigen-1 (Gli1) signaling pathway in mouse Hertwig’s epithelial root sheath (HERS) cells using a genetic knockdown approach. HERS cells treated with a low concentration of cisplatin (0.5 µM) for 24 h showed no reduction in the cell viability; however, there was a significant increase in the percentages of nuclear staining with γH2AX as compared to that with untreated control cells, indicating that 0.5 µM cisplatin induces DNA damage. Further, 0.5-µM cisplatin-treated cells provided an induction of EMT, showing decreased and increased expression of epithelial and mesenchymal markers, respectively. Enhancement in the EMT activity in cisplatin-treated HERS cells was correlated with increased expression of Shh and accelerated translocation and accumulation of Gli1 expression into the nucleus. The RNA interference-mediated silencing of Gli1 suppressed the acceleration of EMT in cisplatin-treated HERS cells; this was confirmed by no down-regulation or up-regelation in the expression of E-cadherin and vimentin, respectively, along with no increased expression of Snail expression. These findings suggest that the activation of Shh/Gli1 signaling pathway may be required for the enhancement of EMT in cisplatin-treated HERS cells.</p>

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