Matrix metalloproteinase 12 overexpression in lung epithelial cells plays a key role in emphysema to lung bronchioalveolar adenocarcinoma transition.
Matrix metalloproteinase 12 overexpression in lung epithelial cells plays a key role in emphysema to lung bronchioalveolar adenocarcinoma transition.
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DOI：
10.1158/0008-5472.can-09-0577
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发表时间：
2009-09-15
期刊：
影响因子：
11.2
通讯作者：
Yan C
中科院分区：
文献类型：
--
作者：
Qu P;Du H;Wang X;Yan C
慢性阻塞性肺疾病（COPD）和肺癌是两种与吸烟有关的疾病。这两种疾病之间的分子机制尚不清楚。基质金属蛋白酶12（MMP 12）是基质金属蛋白酶家族的成员，吸烟可诱导MMP 12表达。由于在炎症触发的肺重塑中已经报道了上皮细胞中的MMP 12过表达，因此建立了鼠CCSP-rtTA/（tetO）7-MMP 12双转基因模型。在该模型中，在肺中以诱导方式观察到MMP 12-Flag融合蛋白过表达及其酶活性增加，这导致炎性细胞浸润和上皮生长增加。在连续事件中，自发性肺气肿和细支气管肺泡腺癌是MMP 12过度表达的结果。在此过程中，支气管肺泡灌洗液中IL-6的浓度稳步增加，激活了肺泡II型上皮细胞中的致癌性Stat 3。已知刺激炎症和肿瘤形成的Stat 3下游基因的表达在肺中显著增加。当在人体中进行测试时，MMP 12上调与患者的COPD和肺癌高度相关。总之，这些研究支持MMP 12是一种有效的促炎和致癌分子。MMP 12上调在肺气肿向肺癌转变中起关键作用，肺气肿向肺癌转变由肺部炎症促进。
Chronic obstructive pulmonary disease (COPD) and lung cancer are two diseases that are related to smoking in humans. The molecular mechanism linking these two diseases is poorly understood. Matrix metalloproteinase 12 (MMP12) is a member of the matrix-metalloproteinase family, which can be induced by smoking. Since MMP12 overexpression in epithelial cells has been reported in inflammation-triggered lung remodeling, a murine CCSP-rtTA/(tetO)7-MMP12 bitransgenic model was created. In this model, MMP12-Flag fusion protein overexpression and its increased enzymatic activity were observed in the lung in an inducible manner, which led to inflammatory cell infiltration and increased epithelial growth. In sequential events, spontaneous emphysema and bronchioalveolar adenocarcinoma were developed as a result of MMP12 overexpression. During this process, the concentration of IL-6 was steadily increased in bronchioalveolar lavage fluid, which activated the oncogenic Stat3 in alveolar type II epithelial cells. Expression of Stat3 downstream genes that are knownto stimulate inflammation and tumor formation was significantly increased in the lung. When tested in humans, MMP12 up-regulation was highly associated with COPD and lung cancer in patients. Together, these studies support that MMP12 is a potent pro-inflammatory and oncogenic molecule. MMP12 up-regulation plays a critical role in emphysema to lung cancer transition that is facilitated by pulmonary inflammation.