The LIM-domain only protein 4 contributes to lung epithelial cell proliferation but is not essential for tumor progression
The LIM-domain only protein 4 contributes to lung epithelial cell proliferation but is not essential for tumor progression
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DOI：
10.1186/s12931-015-0228-0
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发表时间：
2015-06-07
影响因子：
5.8
通讯作者：
Asselin-Labat, Marie-Liesse
中科院分区：
文献类型：
--
作者：
Holik, Aliaksei Z.;Filby, Caitlin E.;Asselin-Labat, Marie-Liesse
背景：肺不断暴露于环境挑战，必须对外部损伤做出快速反应。受损肺的修复机制涉及不同上皮细胞的扩增以重新填充受损的细胞区室。然而，调节肺损伤后细胞增殖的因素仍然知之甚少。在这里，我们研究了肺发育过程中的转录调节因子Lmo 4的作用，在成年肺上皮细胞增殖的调节肺损伤后，并在致癌transformation.Methods的背景下：为了研究Lmo 4在胚胎肺发育，肺修复和肿瘤发生中的作用，我们使用条件性基因敲除小鼠删除Lmo 4在肺上皮细胞从肺发育的第一阶段。使用两种涉及化学和病毒损伤的肺损伤实验模型评估Lmo 4在肺修复中的作用。使用肺腺癌小鼠模型测量Lmo 4在肺肿瘤发生中的作用，其中致癌K-Ras蛋白已敲入K-Ras基因座。通过对数秩检验检验基因型之间的总生存率差异。均数之间的差异进行了测试，使用单向方差分析后，确保假设的正态性和平等的方差satisfied.Results：我们发现，LMO 4是不需要正常的胚胎肺形态发生。在成人肺中，Lmo 4的丢失减少了上皮细胞增殖，延迟了萘或流感介导的损伤后肺的修复，这表明Lmo 4参与了上皮细胞扩增的调节，以响应细胞损伤。在K-Ras（G12 D）驱动的肺肿瘤形成的背景下，Lmo 4丢失并没有改变萘损伤致敏的K-Ras（G12 D）小鼠的总生存率，但延迟了肺增生的开始。最后，我们评估了LMO 4在早期非小细胞肺癌组织微阵列中的表达，并观察到LMO 4在肺鳞癌中的表达高于腺癌。总之，这些结果表明，转录调节因子Lmo 4参与了损伤和致癌转化背景下肺上皮细胞增殖的调节，但Lmo 4的缺失不是足以防止肺修复或肿瘤形成。
Background: The lung is constantly exposed to environmental challenges and must rapidly respond to external insults. Mechanisms involved in the repair of the damaged lung involve expansion of different epithelial cells to repopulate the injured cellular compartment. However, factors regulating cell proliferation following lung injury remain poorly understood. Here we studied the role of the transcriptional regulator Lmo4 during lung development, in the regulation of adult lung epithelial cell proliferation following lung damage and in the context of oncogenic transformation.Methods: To study the role of Lmo4 in embryonic lung development, lung repair and tumorigenesis, we used conditional knock-out mice to delete Lmo4 in lung epithelial cells from the first stages of lung development. The role of Lmo4 in lung repair was evaluated using two experimental models of lung damage involving chemical and viral injury. The role of Lmo4 in lung tumorigenesis was measured using a mouse model of lung adenocarcinoma in which the oncogenic K-Ras protein has been knocked into the K-Ras locus. Overall survival difference between genotypes was tested by log rank test. Difference between means was tested using one-way ANOVA after assuring that assumptions of normality and equality of variance were satisfied.Results: We found that Lmo4 was not required for normal embryonic lung morphogenesis. In the adult lung, loss of Lmo4 reduced epithelial cell proliferation and delayed repair of the lung following naphthalene or flu-mediated injury, suggesting that Lmo4 participates in the regulation of epithelial cell expansion in response to cellular damage. In the context of K-Ras(G12D)-driven lung tumor formation, Lmo4 loss did not alter overall survival but delayed initiation of lung hyperplasia in K-Ras(G12D) mice sensitized by naphthalene injury. Finally, we evaluated the expression of LMO4 in tissue microarrays of early stage non-small cell lung cancer and observed that LMO4 is more highly expressed in lung squamous cell carcinoma compared to adenocarcinoma.Conclusions: Together these results show that the transcriptional regulator Lmo4 participates in the regulation of lung epithelial cell proliferation in the context of injury and oncogenic transformation but that Lmo4 depletion is not sufficient to prevent lung repair or tumour formation.