title: Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1.
abstract: Emerging evidence, although currently very sparse, suggests the presence of "lineage-specific dependency" in the survival mechanisms of certain cancers. TTF-1 has a decisive role as a master regulatory transcription factor in lung development and in the maintenance of the functions of terminal respiratory unit (TRU) cells. We show that a subset of lung adenocarcinoma cell lines expressing TTF-1, which presumably represent those derived from the TRU lineage, exhibit marked dependence on the persistent expression of TTF-1. The inhibition of TTF-1 by RNA interference (RNAi) significantly and specifically induced growth inhibition and apoptosis in these adenocarcinoma cell lines. Furthermore, a fraction of TTF-1-expressing tumors and cell lines displayed an increase in the gene dosage of TTF-1 in the analysis of 214 patients with non-small-cell lung cancer, including 174 adenocarcinomas, showing a tendency of higher frequency of increased gene copies at metastatic sites than at primary sites (P=0.07, by two-sided Fisher's exact test). These findings strongly suggest that in addition to the development and maintenance of TRU lineages in normal lung, sustained TTF-1 expression may be crucial for the survival of a subset of adenocarcinomas that express TTF-1, providing credence for the lineage-specific dependency model.
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yanagisawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Shinjo
authors.forename: Ayumu
authors.initials: A
authors.lastname: Taguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Maeno
authors.forename: Shuta
authors.initials: S
authors.lastname: Tomida
authors.forename: Yukako
authors.initials: Y
authors.lastname: Shimada
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Osada
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kosaka
authors.forename: Hideo
authors.initials: H
authors.lastname: Matsubara
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D045744:Cell Line, Tumor; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008168:Lung / Q000473:pathology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism*; D034622:RNA Interference; D013234:Stem Cells; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors