Cancer Research於6月16日在線發表了中國科學院上海生命科學研究院生物化學與細胞生物學研究所宋建國研究組的一項最新研究成果，胚胎發育及生物個體的各個時期的某些上皮細胞，喪失其上皮細胞形態和特徵，獲得間充質細胞形態和特徵，從而運動遷移能力得到增強。這種表型的轉化被稱為上皮細胞向間充質細胞的轉變 (epithelial-mesenchymal transition，EMT)。EMT是胚胎早期發育和器官生成過程中的重要現象，參與造腸運動、神經脊細胞從神經管的遷移運動，以及心血管瓣膜的形成。成體組織的損傷修復，腎臟、肝臟、肺的纖維化，尤其是惡性腫瘤的浸潤和轉移，都與EMT緊密相關。
宋建國研究組應用比較蛋白質組學方法對轉化生長因子（TGF）-β1誘導的EMT進行了研究，找到36個差異表達的蛋白，絕大多數在EMT中的功能是不明確的，屬於新的發現。鐵蛋白最初被發現的主要功能是作為細胞內鐵離子穩態的調控蛋白。研究發現TGF-β1下調鐵蛋白重鏈及其導致的可變鐵庫的增加在EMT過程中起到關鍵的作用，並顯示了TGF-β1通過3』UTR依賴性的翻譯抑制作用而下調FHC的機制。研究結果還提示鐵蛋白以及可變鐵庫的增加可能與腫瘤的發展以及浸潤遷移能力有一定的關係。在EMT調控機制方面，證實了活性氧分子 (reactive oxygen species, ROS) 在EMT中的作用以及細胞內上調ROS的機制，並且闡明了ROS參與EMT是通過了調控p38 MAPK的機制。此外，進一步證實了細胞發生凋亡和EMT是兩個獨立的事件。因而，對其中一個事件加以控制是具備可能性的。考慮到在腫瘤發生過程中，凋亡和EMT對腫瘤細胞的截然不同的貢獻，這種控制具有一定潛在的應用價值。
該研究工作有助於深入的了解TGF-β多效性和EMT發生的機制，以及TGF-β和EMT在促進癌症發展中的作用與細胞鐵離子代謝之間的關係，為癌症和癌細胞轉移的治療策略提供了新的思路。
該項研究工作得到了國家科技部、基金委 、中國科學院和上海市科委的經費支持。（生物谷Bioon.com）
生物谷推薦原始出處：
Cancer Research, 10.1158/0008-5472.CAN-09-0112
Ferritin Heavy Chain–Mediated Iron Homeostasis and Subsequent Increased Reactive Oxygen Species Production Are Essential for Epithelial-Mesenchymal Transition
Ke-Hua Zhang 1, Hong-Yu Tian 1, Xia Gao 1, Wei-Wei Lei 1, Ying Hu 1, Dong-Mei Wang 1, Xin-Chao Pan 1, Mei-Lan Yu 2, Gen-Jun Xu 1, 2, Fu-Kun Zhao 1, 2, and Jian-Guo Song 1*
1Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China and 2College of Life Science, Zhejiang Sci-Tech University, Hangzhou, China
The epithelial-mesenchymal transition (EMT) plays a critical role in tumor progression. To obtain a broad view of the molecules involved in EMT, we carried out a comparative proteomic analysis of transforming growth factor-β1 (TGF-β1)–induced EMT in AML-12 murine hepatocytes. A total of 36 proteins with significant alterations in abundance were identified. Among these proteins, ferritin heavy chain (FHC), a cellular iron storage protein, was characterized as a novel modulator in TGF-β1–induced EMT. In response to TGF-1, there was a dramatic decrease in the FHC levels, which caused iron release from FHC and, therefore, increased the intracellular labile iron pool (LIP). Abolishing the increase in LIP blocked TGF-β1–induced EMT. In addition, increased LIP levels promoted the production of reactive oxygen species (ROS), which in turn activated p38 mitogen-activated protein kinase. The elimination of ROS inhibited EMT, whereas H2O2 treatment rescued TGF-1–induced EMT in cells in which the LIP increase was abrogated. Overexpression of exogenous FHC attenuated the increases in LIP and ROS production, leading to a suppression of EMT. We also showed that TGF-1–mediated down-regulation of FHC occurs via 3' untranslated region–dependent repression of the translation of FHC mRNA. Moreover, we found that FHC down-regulation is an event that occurs between the early and highly invasive advanced stages in esophageal adenocarcinoma and that depletion of LIP or ROS suppresses the migration of tumor cells. Our data show that cellular iron homeostasis regulated by FHC plays a critical role in TGF-1–induced EMT.