近日,，國(guó)際腫瘤研究領(lǐng)域權(quán)威雜志《癌癥研究》 Cancer Research 在線發(fā)表了中科院上海生命科學(xué)研究院營(yíng)養(yǎng)所陳雁研究組的最新研究進(jìn)展，揭示了RKTG與p53在腫瘤發(fā)生及上皮細(xì)胞間質(zhì)轉(zhuǎn)型（EMT）方面的協(xié)同功能,。
陳雁課題組近年來(lái)集中在RKTG的研究,。在前期工作中，他們發(fā)現(xiàn)了RKTG是一個(gè)對(duì)Ras到ERK信號(hào)通路進(jìn)行空間調(diào)控的蛋白,，而Ras到ERK的信號(hào)通路參與了多個(gè)關(guān)鍵的細(xì)胞功能,，在腫瘤的形成中尤為重要。他們的一系列工作發(fā)現(xiàn),，RKTG具有抑癌基因的功能,。有意思的是，RKTG基因敲除小鼠不會(huì)自發(fā)形成腫瘤,，而另一方面,，p53作為一個(gè)研究非常深入的抑癌基因，當(dāng)在小鼠中敲除p53以后,，p53雜合小鼠從12個(gè)月才開(kāi)始發(fā)生肉瘤及其它惡性腫瘤,。
陳雁課題組博士生蔣玉輝等人的研究發(fā)現(xiàn)，在RKTG和p53基因雙敲除的雜合小鼠中，從7個(gè)月開(kāi)始就有自發(fā)性的皮膚腫瘤發(fā)生,，并且腫瘤組織上皮有增生和EMT現(xiàn)象,。EMT是介導(dǎo)腫瘤細(xì)胞浸潤(rùn)和轉(zhuǎn)移的最重要環(huán)節(jié)，在一系列的動(dòng)物和細(xì)胞實(shí)驗(yàn)中,，蔣玉輝等人驗(yàn)證了RKTG和p53對(duì)于EMT的發(fā)生都發(fā)揮了關(guān)鍵的功能,。
該研究不僅第一次揭示了RKTG和p53兩個(gè)抑癌基因在腫瘤形成過(guò)程中的協(xié)同功能，還發(fā)現(xiàn)它們參與了腫瘤細(xì)胞的EMT過(guò)程,，并提出p53是一個(gè)調(diào)控EMT的“關(guān)卡”,，只有在這一“關(guān)卡”功能喪失的情況下，腫瘤細(xì)胞才能有效地進(jìn)行EMT,，進(jìn)而參與腫瘤的浸潤(rùn)和轉(zhuǎn)移,。因此，該研究不但深化了對(duì)于腫瘤浸潤(rùn)和轉(zhuǎn)移的認(rèn)識(shí),，也為未來(lái)腫瘤的治療提供了一個(gè)新的理論依據(jù),。
該研究得到中科院、國(guó)家基金委和科技部項(xiàng)目的支持,。（生物谷Bioon.com）
生物谷推薦原文出處：
Cancer Res doi: 10.1158/0008-5472.CAN-10-4077
Functional Cooperation of RKTG with p53 in Tumorigenesis and Epithelial–Mesenchymal Transition
Yuhui Jiang1, Xiaoduo Xie1, Zhigang Li1, Zheng Wang1, Yixuan Zhang1, Zhiqiang Ling2, Yi Pan1, Zhenzhen Wang1, and Yan Chen1
Abstract
Raf kinase trapping to Golgi (RKTG) is a potential tumor suppressor gene due to its negative roles in regulating Ras/Raf/MEK/ERK (extracellular signal–regulated kinase) pathway and GPCR (G protein–coupled receptor) Gβγ subunit signaling. Interestingly, RKTG-deficient mice are free of tumors, although they are prone to form skin cancer on carcinogen administration. On the other hand, p53 is a well-characterized tumor suppressor gene and p53 heterozygous mice develop sarcoma and other tumors starting from 12 months of age. In RKTG-null mouse embryonic fibroblasts, lypophosphatidic acid (LPA), but not EGF (epidermal growth factor), could stimulate hyperphosphorylation of AKT and GSK3β, accompanied by increases in phosphorylation of p53 at Ser15 and accumulation of p53, as well as its target genes p21 and p16. Spontaneous skin cancer–like tumors were detected in about 25% of RKTG nullizygous and p53 heterozygous mice within 7 months of age. Hyperplasia and epithelial–mesenchymal transition (EMT) were observed in the tumor-overlying epidermis, in which LOH of p53 occurred and EMT features emerged. In p53-mutated A431 epithelial carcinoma cells, knockdown of RKTG led to enhancement of LPA-stimulated AKT and GSK3β phosphorylation, together with increased accumulation of β-catenin and appearance of EMT features that were antagonized by p53 overexpression. In HepG2 epithelial cells, LPA-stimulated AKT phosphorylation and EMT features reached maximum when both RKTG and p53 were simultaneously silenced. In summary, these results not only indicate that RKTG has an in vivo tumor suppressor function to cooperate with p53 in tumorigenesis but also suggest that p53 has an EMT checkpoint function and the loss of this function can combine with loss of RKTG to drive EMT and tumor progression.
