Down-regulation and antiproliferative role of C/EBPalpha in lung cancer.
Down-regulation and antiproliferative role of C/EBPalpha in lung cancer.
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发表时间：
2002
期刊：
影响因子：
11.2
通讯作者：
B. Halmos;C. Huettner;O. Kocher;K. Ferenczi;D. Karp;D. Tenen
中科院分区：
文献类型：
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作者：
B. Halmos;C. Huettner;O. Kocher;K. Ferenczi;D. Karp;D. Tenen
转录因子，CCAAT/增强子结合蛋白α (C/EBPalpha)在粒细胞、肝细胞和脂肪细胞的终末分化中很重要，并且在急性髓性白血病中描述了C/EBPalpha的复发突变。在肺中，C/EBPalpha在支气管细胞和II型肺细胞中表达。在C/EBPalpha敲除小鼠中报告了后一种细胞类型的异常增殖。我们用Northern blot法检测了30株肺癌细胞株中C/EBPalpha的表达，发现有24株细胞株中C/EBPalpha的表达显著下调。原发肿瘤标本的免疫组化研究显示，53例标本中有23例未检测到或低表达C/EBPalpha。它的表达在腺癌和低分化癌标本中比在鳞状细胞癌中更经常下调。越晚期，表达减少的频率越高。为了研究C/EBPalpha在肺癌细胞中表达的后果，我们用质粒稳定转染了两种不表达该基因的细胞系（Calu1和H358），从而诱导C/EBPalpha蛋白的表达。C/EBPalpha的诱导导致增殖阻滞、分化特征的形态学改变和细胞凋亡。这些结果表明，C/EBPalpha在大部分肺癌中下调，并且在气道上皮细胞中具有生长抑制特性。C/EBPalpha基因的遗传分析正在进行中，以充分评估其作为一种新的肿瘤抑制因子在肺癌中的作用。
The transcription factor, CCAAT/enhancer binding protein alpha (C/EBPalpha) is important in the terminal differentiation of granulocytes, hepatocytes, and adipocytes, and recurrent mutations of C/EBPalpha were described in acute myeloid leukemia. In the lung, C/EBPalpha is expressed in bronchial cells and type II pneumocytes. Abnormal proliferation of the latter cell type was reported in C/EBPalpha knockout mice. We determined the expression of C/EBPalpha by Northern blot analysis in 30 lung cancer cell lines and found significant down-regulation in 24 cell lines. Immunohistochemical study of primary tumor specimens showed undetectable or low expression of C/EBPalpha in 23 of 53 specimens. Its expression was more frequently down-regulated in adenocarcinoma and poorly differentiated cancer specimens than in squamous cell cancers. A higher frequency of reduced expression was found in more advanced stages. To investigate the consequences of C/EBPalpha expression in lung cancer cells, we stably transfected two cell lines that do not express the gene (Calu1 and H358) with a plasmid allowing for induction of C/EBPalpha protein expression. Induction of C/EBPalpha led to significant growth reduction attributable to proliferation arrest, morphological changes characteristic of differentiation, and apoptosis. These results suggest that C/EBPalpha is down-regulated in a large proportion of lung cancers and that it has growth-inhibitory properties in airway epithelial cells. Genetic analysis of the C/EBPalpha gene is in progress to fully evaluate its role as a novel tumor suppressor in lung cancer.