TY - JOUR
T1 - Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1
AU - Tanaka, Hisaaki
AU - Yanagisawa, Kiyoshi
AU - Shinjo, Keiko
AU - Taguchi, Ayumu
AU - Maeno, Ken
AU - Tomida, Shuta
AU - Shimada, Yukako
AU - Osada, Hirotaka
AU - Kosaka, Takayuki
AU - Matsubara, Hideo
AU - Mitsudomi, Tetsuya
AU - Sekido, Yoshitaka
AU - Tanimoto, Mitsune
AU - Yatabe, Yasushi
AU - Takahashi, Takashi
PY - 2007/7/1
Y1 - 2007/7/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-06-4774
DO - 10.1158/0008-5472.CAN-06-4774
M3 - Article
C2 - 17616654
AN - SCOPUS:34447131535
SN - 0008-5472
VL - 67
SP - 6007
EP - 6011
JO - Cancer Research
JF - Cancer Research
IS - 13
ER -