细胞凋亡和上皮细胞向间质细胞的转变 (Epithelial-Mesenchymal Transition，EMT) 在多种生理和病理过程中起到了重要的作用。细胞凋亡和EMT的失调会导致一些疾病的发生，例如肿瘤的形成和转移、肝脏和肾脏纤维化和胚胎发育的异常等。中国科学院上海生命科学研究院生物化学与细胞生物学研究所宋建国研究组在10月发表的Hepatology上报道了一氧化氮调控TGF-β1诱导的细胞凋亡和上皮细胞向间质细胞转变的作用及相关机制。
在小鼠肝实质细胞中，转化生长因子-β1(Transforming Growth Factor-β，TGF-β1) 可以同时诱导细胞凋亡和EMT两种生物学过程。一氧化氮 (Nitric Oxide, NO) 是一种具有高度反应活性的气体小分子，参与调节肝脏的多种生理病理过程，对肝脏具有重要的保护作用。研究发现：加入外源的NO供体，可以抑制TGF-β1诱导的肝细胞凋亡和EMT。通过细胞转染和细胞内诱导表达等方法提高诱导性NO合成酶（iNOS）的表达和内源性NO的生成，也可以抑制TGF-β1诱导的肝细胞凋亡和EMT，从而进一步证实了NO的作用。进一步的研究工作显示NO可以通过下调细胞内ATP水平和抑制STAT3活化抑制TGF-β1诱导的肝细胞凋亡和EMT。本研究有助于加深对TGF-β1和NO调控细胞凋亡和EMT的机制的认识，并具有潜在的相关的医学临床应用参考价值。
该项研究工作得到了科技部、基金委 、中国科学院和上海市科委的经费支持。（生物谷Bioon.com）
生物谷推荐原始出处：
Hepatology DOI:10.1002/hep.23156
Nitric oxide suppresses transforming growth factor-1-induced epithelial-to-mesenchymal transition and apoptosis in mouse hepatocytes
Xinchao Pan, Xunde Wang, Weiwei Lei, Lihua Min, Yanan Yang, Xin Wang, Jianguo Song *
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P.R. China
Nitric oxide (NO) is a multifunctional regulator that is implicated in various physiological and pathological processes. Here we report that administration of NO donor S-nitroso-N-acetylpenicillamine (SNAP) inhibited transforming growth factor-β1 (TGF-β1)-induced epithelial-to-mesenchymal transition (EMT) and apoptosis in mouse hepatocytes. Overexpression of inducible NO synthase (iNOS) by transfection of the iNOS-expressing vector, which increased NO production, also inhibited the TGF-β1-induced EMT and apoptosis in these cells. Treatment of cells with proinflammatory mediators, including tumor necrosis factor (TNF)-, interleukin (IL)-β1, and interferon (IFN)-β, which increased the endogenous NO production, produced the same inhibitory effect. Furthermore, exogenous NO donor SNAP treatment caused a decrease in the intracellular adenosine triphosphate (ATP) levels. Consistently, depletion of intracellular ATP by mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) inhibited the TGF-β1-induced EMT and apoptosis, suggesting that an NO-induced decrease of ATP involved in the NO-mediated inhibition of TGF-1-induced EMT and apoptosis. NO and FCCP also inhibited TGF-1-induced STAT3 activation, suggesting that signal transducer and activator of transcription 3 inactivation is involved in the NO-induced effects on TGF-1-induced EMT and apoptosis. Conclusion: Our study indicates that NO plays an important role in the inhibition of TGF-1-induced EMT and apoptosis in mouse hepatocytes through the downregulation of intracellular ATP levels. The data provide an insight into the in vivo mechanisms on the function of NO during the processes of both EMT and apoptosis. (HEPATOLOGY 2009.)
