Lineage-specific survival signal of lung adenocarcinoma on the lung

• Project/Area Number: 22790753
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Respiratory organ internal medicine
• Research Institution: Nagoya University
• Principal Investigator: YAMAGUCHI Tomoya 名古屋大学, 大学院・医学系研究科, 助教 (70452191)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 肺腺癌 / TTF-1 / リネジ特異的マスター調節因子 / リネジ特異的シグナル / 発がん / 遊走能 / 浸潤能 / 転移能 / リネッジ特異的マスター調節因子 / リネッジ特異的シグナル / 発癌

Research Abstract

Sustained TTF-1 expression plays a crucial role in the survival of lung adenocarcinoma, in addition to the development and maintenance of cell lineages in normal lung. In this study, we identified DOT-2, as a TTF-1-regulated gene, and we showed that DOT-2 inhibited assembly competence-conferring phosphorylation of the myosin regulatory light chain(RLC) as well as activating phosphorylation of LIM domain kinase(LIMK), unexpectedly through its direct physical interaction with Rho kinase 1(ROCK1) rather than with RLC. Consequently, DOT-2 inhibited ROCK1 and negatively regulated actomyosin organization, which in turn reduced single cell motility and increased collective cell migration, resulting in decreased cancer invasion and metastasis. Finally, we also show that DOT-2 is epigenetically inactivated by promoter DNA methylation in a fraction of TTF-1-positive lung adenocarcinomas, which appears to be in accordance with its deleterious functions in lung adenocarcinoma invasion and metastasis, as well as with the paradoxical association of TTF-1 expression with favourable prognosis in lung adenocarcinoma patients.

Research Products

• [Journal Article] MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis (2012)
  • Author(s): Yasuyuki Hosono, Tomoya Yamaguchi, Eri Mizutani, Kiyoshi Yanagisawa, Chinatsu Arima, Shuta Tomida, Yukako Shimada, Michiyo Hiraoka, Seiichi Kato, Kohei Yokoi, Motoshi Suzuki, Takashi Takahashi
  • Journal Title: The EMBO Journal Volume: 31 Pages: 481-193
  • Peer Reviewed
• [Journal Article] NKX2-1/TITF1/TTF-1-Induced ROR1 Is Required to Sustain EGFR Survival Signaling in Lung Adenocarcinoma (2012)
  • Author(s): Tomoya Yamaguchi, Kiyoshi Yanagisawa, Ryoji Sugiyama, Yasuyuki Hosono, Yukako Shimada, Chinatsu Arima, Seiichi Kato, Shuta Tomida, Motoshi Suzuki, Hirotaka Osada, Takashi Takahashi
  • Journal Title: Cancer Cell Volume: (in press)
  • Peer Reviewed
• [Journal Article] MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis (2012)
  • Author(s): Hosono Y, et al
  • Journal Title: EMBO Journal Volume: 31 Issue: 2 Pages: 481-493
  • DOI: 10.1038/emboj.2011.416
  • Peer Reviewed
• [Journal Article] NKX2-1/TITF1/TTF-1-Induced ROR1 Is Required to Sustain EGFR Survival Signaling in Lung Adenocarcinoma (2012)
  • Author(s): 山口知也
  • Journal Title: Cancer Cell Volume: (印刷中)(in press)
  • Peer Reviewed
• [Remarks]
  • URL: http://www.med.nagoya-u.ac.jp/molcar/jp/
• [Remarks]
  • URL: http://www.med.nagoya-u.ac.jp/molcar/jp/