6月4日Cancer Research雜志在線報(bào)道了一種新開(kāi)發(fā)的缺氧感受信號(hào)通路斑馬魚(yú)體內(nèi)研究系統(tǒng),，為深入研究缺氧在腫瘤中作用提供了有力的新手段。
缺氧信號(hào)通路是腫瘤細(xì)胞病理過(guò)程的核心調(diào)控者,。過(guò)去對(duì)氧濃度感受途徑的關(guān)鍵因子von Hippel-Lindau腫瘤抑制蛋白（pVHL）以及HIF轉(zhuǎn)錄因子雖然研究得很多,，但是還需要加強(qiáng)在生物模型中對(duì)缺氧途徑的研究,，以加深人類(lèi)對(duì)腫瘤病理的理解，促進(jìn)新治療手段的研發(fā),。
為此,，研究者試圖用斑馬魚(yú)模式生物研究HIF信號(hào)通路在腫瘤起源和發(fā)展中的作用。他們開(kāi)發(fā)出一種獨(dú)特的體內(nèi)缺氧報(bào)告系統(tǒng),，可在缺氧誘導(dǎo)因子脯氨酰羥化酶3（phd3）啟動(dòng)/調(diào)節(jié)元件的驅(qū)動(dòng)下表達(dá)EGFP,。在Tg(phd3::EGFP)斑馬魚(yú)胚胎中的研究顯示，斑馬魚(yú)vhl突變體表現(xiàn)出系統(tǒng)性的缺氧反應(yīng),。在缺氧反應(yīng)途徑成員脯氨酰羥化酶3（phd3）啟動(dòng)/調(diào)節(jié)元件驅(qū)動(dòng)下,，轉(zhuǎn)基因EGFP呈現(xiàn)強(qiáng)烈而廣泛的表達(dá)。
與人類(lèi)VHL患者不同的是,，雜合子Vhl小鼠和vhl斑馬魚(yú)均未表現(xiàn)對(duì)腫瘤的特殊易感性,。然而，在暴露于化學(xué)致癌劑二甲基苯并蒽（DMBA）情況下,，vhl雜合子斑馬魚(yú)的肝及腸道腫瘤的發(fā)生率上升了,。而且，其中部分腫瘤細(xì)胞呈現(xiàn)較強(qiáng)的EGFP表達(dá),，提示Vhl在其中的功能丟失,。與對(duì)照組相比，DMBA處理的vhl雜合子斑馬魚(yú)在腎小管中增殖細(xì)胞核抗原陽(yáng)性率也增加了,。
總之,，該研究證實(shí)了Vhl在斑馬魚(yú)模型中確為腫瘤抑制因子，并為非損傷性研究VHL和HIF信號(hào)通路在腫瘤發(fā)生和發(fā)展中的作用通過(guò)了可靠的模型,。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
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A zebrafish model to study and therapeutically manipulate hypoxia signaling in tumorigenesis
Kirankumar Santhakumar1, Emma C Judson1, Philip M Elks1, Sarah McKee1, Stone Elworthy1, Ellen van Rooijen2, Sarah S Walmsley3, Stephen Renshaw4, Simon S. Cross5, and Fredericus JM van Eeden6,*
Abstract
Hypoxic signaling is a central modulator of cellular physiology in cancer. Core members of oxygen sensing pathway including the von Hippel-Lindau tumor suppressor protein (pVHL) and the HIF transcription factors have been intensively studied, but improved organismal models might speed advances for both pathobiological understanding and therapeutic modulation. To study HIF signaling during tumorigenesis and development in zebrafish, we developed a unique in vivo reporter for hypoxia, expressing EGFP driven by prolyl hydroxylase 3 (phd3) promoter/regulatory elements. Modulation of HIF pathway in Tg(phd3::EGFP) embryos showed a specific role for hypoxic signaling in the transgene activation. Zebrafish vhl mutants display a systemic hypoxia response, reflected by strong and ubiquitous transgene expression. In contrast to human VHL patients, heterozygous Vhl mice and vhl zebrafish are not predisposed to cancer. However, upon exposure to dimethylbenzanthracene (DMBA), the vhl heterozygous fish showed an increase in the occurrence of hepatic and intestinal tumors, a subset of which exhibited strong transgene expression, suggesting loss of Vhl function in these tumor cells. Compared to control fish, DMBA-treated vhl heterozygous fish also showed an increase in proliferating cell nuclear antigen positive renal tubules. Taken together, our findings establish Vhl as a genuine tumor suppressor in zebrafish and offer this model as a tool to non-invasively study VHL and HIF signaling during tumorigenesis and development.
