Lineage-specific survival signal of lung adenocarcinoma on the lung

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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.