Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1
Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1
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DOI：
10.1158/0008-5472.can-06-4774
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发表时间：
2007-07-01
期刊：
影响因子：
11.2
通讯作者：
Takahashi, Takashi
中科院分区：
文献类型：
--
作者：
Tanaka, Hisaaki;Yanagisawa, Kiyoshi;Takahashi, Takashi
新出现的证据，虽然目前非常稀少，表明在某些癌症的生存机制中存在“谱系特异性依赖”。TTF-1在肺发育和维持终末呼吸单位（TRU）细胞功能中作为主调节转录因子具有决定性作用。我们表明，一个子集的肺腺癌细胞系表达TTF-1，这可能代表那些来自TRU谱系，表现出显着的依赖性TTF-1的持续表达。通过RNA干扰（RNAi）抑制TTF-1显著且特异性地诱导这些腺癌细胞系的生长抑制和凋亡。此外，在对214例非小细胞肺癌患者（包括174例腺癌）的分析中，一部分TTF-1表达肿瘤和细胞系显示TTF-1基因剂量增加，显示转移部位基因拷贝增加频率高于原发部位的趋势（P = 0.07，双侧Fisher精确检验）。这些发现强烈表明，除了在正常肺中形成和维持TRU谱系外，持续的TTF-1表达可能对表达TTF-1的腺癌亚组的存活至关重要，为谱系特异性依赖模型提供了证据。
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.