Wang Xiao-Yang, Dakir El Habib, Naizhen Xu, Jensen-Taubman Sandra M, DeMayo Francesco J, Linnoila R Ilona
Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Lab Invest. 2007 Jun;87(6):527-39. doi: 10.1038/labinvest.3700552.
The basic helix-loop-helix protein achaete-scute homolog-1 (ASH1) is involved in lung neuroendocrine (NE) differentiation and tumor promotion in SV40 transgenic mice. Constitutive expression of human ASH-1 (hASH1) in mouse lung results in hyperplasia and remodeling that mimics bronchiolization of alveoli (BOA), a potentially premalignant lesion of human lung carcinomas. We now show that this is due to sustained cellular proliferation in terminal bronchioles and resistance to apoptosis. Throughout the airway epithelium the expression of anti-apoptotic Bcl-2 and c-Myb was increased and Akt/mTOR pathway activated. Moreover, the expression of matrix metalloproteases (MMPs) including MMP7 was specifically enhanced at the bronchiolo-alveolar duct junction and BOA suggesting that MMPs play a key role in this microenvironment during remodeling. We also detected MMP7 in 70% of human BOA lesions. Knockdown of hASH1 gene in human lung cancer cells in vitro suppressed growth by increasing apoptosis. We also show that forced expression of hASH1 in immortalized human bronchial epithelial cells decreases apoptosis. We conclude that the impact of hASH1 is not limited to cells with NE phenotype. Rather, constitutive expression of hASH1 in lung epithelium promotes remodeling through multiple pathways that are commonly activated during lung carcinogenesis. The collective results suggest a novel model of BOA formation via hASH1-induced suppression of the apoptotic pathway. Our study yields a promising new preclinical tool for chemoprevention of peripheral lung carcinomas.
碱性螺旋-环-螺旋蛋白achaete-scute同源物1（ASH1）参与SV40转基因小鼠的肺神经内分泌（NE）分化和肿瘤促进过程。人ASH-1（hASH1）在小鼠肺中的组成性表达导致增生和重塑，类似于肺泡细支气管化（BOA），这是人类肺癌的一种潜在癌前病变。我们现在表明，这是由于终末细支气管中细胞持续增殖以及对细胞凋亡的抵抗。在整个气道上皮中，抗凋亡蛋白Bcl-2和c-Myb的表达增加，Akt/mTOR信号通路被激活。此外，包括MMP7在内的基质金属蛋白酶（MMPs）的表达在细支气管-肺泡管连接处和BOA处特异性增强，这表明MMPs在重塑过程中的这种微环境中起关键作用。我们还在70%的人类BOA病变中检测到MMP7。体外敲低人肺癌细胞中的hASH1基因可通过增加细胞凋亡来抑制生长。我们还表明，在永生化的人支气管上皮细胞中强制表达hASH1可减少细胞凋亡。我们得出结论，hASH1的影响不限于具有NE表型的细胞。相反，hASH1在肺上皮中的组成性表达通过肺癌发生过程中通常被激活的多种途径促进重塑。这些综合结果提示了一种通过hASH1诱导的凋亡途径抑制形成BOA的新模型。我们的研究产生了一种有前景的新的临床前工具，用于外周肺癌的化学预防。
