Dakir E L Habib, Feigenbaum Lionel, Linnoila R Ilona
Experimental Pathology Section, Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Carcinogenesis. 2008 Dec;29(12):2377-84. doi: 10.1093/carcin/bgn190. Epub 2008 Aug 12.
Squamous cell carcinoma accounts for 20% of all human lung cancers and is strongly linked to cigarette smoking. It develops through premalignant changes that are characterized by high levels of keratin 14 (K14) expression in the airway epithelium and evolve through basal cell hyperplasia, squamous metaplasia and dysplasia to carcinoma in situ and invasive carcinoma. In order to explore the impact of K14 in the pulmonary epithelium that normally lacks both squamous differentiation and K14 expression, human keratin 14 gene hK14 was constitutively expressed in mouse airway progenitor cells using a mouse Clara cell specific 10 kDa protein (CC10) promoter. While the lungs of CC10-hK14 transgenic mice developed normally, we detected increased expression of K14 and the molecular markers of squamous differentiation program such as involucrin, loricrin, small proline-rich protein 1A, transglutaminase 1 and cholesterol sulfotransferase 2B1. In contrast, wild-type lungs were negative. Aging CC10-hK14 mice revealed multifocal airway cell hyperplasia, occasional squamous metaplasia and their lung tumors displayed evidence for multidirectional differentiation. We conclude that constitutive expression of hK14 initiates squamous differentiation program in the mouse lung, but fails to promote squamous maturation. Our study provides a novel model for assessing the mechanisms of premalignant lesions in vivo by modifying differentiation and proliferation of airway progenitor cells.
鳞状细胞癌占人类肺癌总数的20%，与吸烟密切相关。它通过癌前病变发展而来，其特征是气道上皮中角蛋白14（K14）表达水平较高，并通过基底细胞增生、鳞状化生和发育异常演变为原位癌和浸润癌。为了探究K14在正常情况下缺乏鳞状分化和K14表达的肺上皮中的影响，使用小鼠克拉拉细胞特异性10 kDa蛋白（CC10）启动子在小鼠气道祖细胞中组成性表达人角蛋白14基因hK14。虽然CC10-hK14转基因小鼠的肺正常发育，但我们检测到K14以及鳞状分化程序的分子标志物如内披蛋白、兜甲蛋白、富含脯氨酸的小分子蛋白1A、转谷氨酰胺酶1和胆固醇硫酸转移酶2B1的表达增加。相比之下，野生型肺呈阴性。衰老的CC10-hK14小鼠显示多灶性气道细胞增生、偶尔的鳞状化生，并且它们的肺肿瘤表现出多向分化的证据。我们得出结论，hK14的组成性表达启动了小鼠肺中的鳞状分化程序，但未能促进鳞状成熟。我们的研究提供了一个通过改变气道祖细胞的分化和增殖来评估体内癌前病变机制的新模型。
