Lineage-specific survival signal of lung adenocarcinoma on the lung

肺腺癌谱系特异性生存信号

• 批准号: 22790753
• 负责人: YAMAGUCHI Tomoya
• 金额: $ 2.5万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22790753/
• 关键词: 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

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.

TTF-1的持续表达在肺腺癌的生存中起着至关重要的作用，除了正常肺中细胞谱系的发育和维持之外。在这项研究中，我们确定了DOT-2，作为TTF-1调节基因，我们表明，DOT-2抑制组装能力赋予磷酸化的肌球蛋白调节轻链（RLC）以及激活磷酸化的LIM结构域激酶（LIMK），出乎意料地通过其直接的物理相互作用与Rho激酶1（ROCK 1），而不是与RLC。因此，DOT-2抑制ROCK 1并负调节肌动球蛋白组织，这反过来又降低了单个细胞的运动性并增加了集体细胞迁移，从而降低了癌症的侵袭和转移。最后，我们还表明，DOT-2是表观遗传失活的启动子DNA甲基化的一部分TTF-1阳性肺腺癌，这似乎是根据其有害的功能，肺腺癌的侵袭和转移，以及矛盾的关联TTF-1表达与肺腺癌患者的良好预后。

项目成果

NKX2-1/TITF1/TTF-1-Induced ROR1 Is Required to Sustain EGFR Survival Signaling in Lung Adenocarcinoma

• DOI: 10.1016/j.ccr.2012.02.008
• 发表时间: 2012-03-20
• 期刊: CANCER CELL
• 影响因子: 50.3
• 作者: Yamaguchi, Tomoya;Yanagisawa, Kiyoshi;Takahashi, Takashi
• 通讯作者: Takahashi, Takashi

MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis

• DOI: 10.1038/emboj.2011.416
• 发表时间: 2012-01-18
• 期刊: EMBO JOURNAL
• 影响因子: 11.4
• 作者: Hosono, Yasuyuki;Yamaguchi, Tomoya;Takahashi, Takashi
• 通讯作者: Takahashi, Takashi