Department of Integrated Chinese and Western Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Eur Rev Med Pharmacol Sci. 2018 Sep;22(18):5980-5986. doi: 10.26355/eurrev_201809_15932.
p38 MAPK are a class of protein kinase that may induce or prevent apoptosis in different circumstance. Emerging researches show that it plays a vital role in tumor progression and therefore understanding its dual role in different stages of lung cancer are important to investigate. Also in this study, we planned to understand its upstream target proteins like HDAC1 and uPAR which are responsible for p38 MAPK activation in the pathway.
We initially develop lung cancer mice model by exposing them to high nicotine content tobacco smoke. The pathological stages of initial and advanced lung cancer are observed and confirmed through histological sectioning. The expression of HDAC1, uPAR and p38 MAPK are observed and analyzed in different stages of lung cancer using immunohistochemistry and Western blotting.
After 4 and 6 months of regular exposure of high nicotine content smoke, the A/J strain mice develop initial and advanced stage of lung cancer. The initial stage cancer develops thick tissue layers with fibrosis whereas advanced stages of lung cancer show more proliferative cells. The expression of HDAC1 and uPAR shows the minimal expression pattern in control and initial stages of lung cancer, but its expression increased in advanced stage of cancer. In case of phospho-p38 MAPK, mild expression was observed almost in every individual cell in the initial stages of cancer, which implies its protective role in preventing advanced stage of cancer. But in advanced stage of lung cancer, we observed dysregulated overexpression of phospho-p38 MAPK.
The epigenetic regulation of uPAR by HDAC1 confirms its indirect role in regulating p38 MAPK as tumor progress.
p38 MAPK 是一类蛋白激酶，在不同的环境下可能诱导或阻止细胞凋亡。新的研究表明，它在肿瘤进展中起着至关重要的作用，因此了解其在肺癌不同阶段的双重作用对于研究它是很重要的。此外，在这项研究中，我们计划了解其上游靶蛋白，如负责 p38 MAPK 通路激活的 HDAC1 和 uPAR。
我们首先通过使 A/J 品系小鼠暴露于高尼古丁含量的烟雾中来建立肺癌小鼠模型。通过组织切片观察和确认肺癌的初始和晚期阶段的病理变化。使用免疫组织化学和 Western blot 分析在不同阶段的肺癌中观察和分析 HDAC1、uPAR 和 p38 MAPK 的表达。
经过 4 个月和 6 个月的定期高尼古丁含量烟雾暴露，A/J 品系小鼠发展出肺癌的初始和晚期阶段。早期肺癌发展出厚的组织层和纤维化，而晚期肺癌则显示出更多的增殖细胞。HDAC1 和 uPAR 的表达在对照和肺癌的初始阶段表现出最小的表达模式，但在癌症的晚期阶段表达增加。对于磷酸化 p38 MAPK，在癌症的初始阶段，几乎每个细胞都观察到轻度表达，这表明它在防止癌症晚期方面具有保护作用。但是在肺癌的晚期阶段，我们观察到磷酸化 p38 MAPK 的失调过表达。
HDAC1 对 uPAR 的表观遗传调控证实了其在调节 p38 MAPK 作为肿瘤进展中的间接作用。
