Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1.
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.
Tanaka
Hisaaki
H
Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yanagisawa
Kiyoshi
K
Shinjo
Keiko
K
Taguchi
Ayumu
A
Maeno
Ken
K
Tomida
Shuta
S
Shimada
Yukako
Y
Osada
Hirotaka
H
Kosaka
Takayuki
T
Matsubara
Hideo
H
Mitsudomi
Tetsuya
T
Sekido
Yoshitaka
Y
Tanimoto
Mitsune
M
Yatabe
Yasushi
Y
Takahashi
Takashi
T
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*
D004268:DNA-Binding Proteins; C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors