近日,，國(guó)際著名雜志Carcinogenesis刊登了廈門(mén)大學(xué)生命科學(xué)學(xué)院的吳喬教授研究團(tuán)隊(duì)的最新研究成果“Orphan receptor TR3 participates in cisplatin-induced apoptosis via Chk2 phosphorylation to repress intestinal tumorigenesis,。”，吳喬教授的主要研究領(lǐng)域是核受體的作用機(jī)理和細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)調(diào)控,、以核受體為靶點(diǎn)的抗腫瘤和代謝性疾病藥物研究。
孤兒受體是指一類目前還未發(fā)現(xiàn)其相應(yīng)配體的核受體，這些受體能和特定DNA上的應(yīng)答元件結(jié)合,，調(diào)控特定基因的表達(dá)，從而在細(xì)胞的生長(zhǎng),、分化和凋亡等生物學(xué)過(guò)程中發(fā)揮重要的調(diào)節(jié)作用,。TR3也被稱為Nur77，是一種立刻早期基因（immediateearlygene）的產(chǎn)物,，與固醇類激素受體結(jié)構(gòu)相似,，是核受體超家族的重要成員之一，可被血清及表皮生長(zhǎng)因子,、神經(jīng)生長(zhǎng)因子,、血小板生長(zhǎng)因子等誘導(dǎo)表達(dá)，具有復(fù)雜的生物學(xué)功能,，涉及細(xì)胞增殖,、分化發(fā)育和凋亡等過(guò)程。
在這論文中,，研究人員發(fā)現(xiàn)現(xiàn)在腫瘤治療一線藥物順鉑刺激下,，核孤兒受體TR3發(fā)生磷酸化修飾，并在腸癌細(xì)胞的凋亡過(guò)程中發(fā)揮重要作用,。機(jī)理分析表明,，順鉑首先激活細(xì)胞周期檢控點(diǎn)激酶Chk2，TR3的T88位點(diǎn)在該激酶的作用下發(fā)生磷酸化,，蛋白穩(wěn)定性增強(qiáng),，同時(shí)，發(fā)生磷酸化修飾的TR3還能夠募集轉(zhuǎn)錄輔抑制因子N-CoR,，通過(guò)結(jié)合到下游基因BRE和RNF-7 promoter的TR3應(yīng)答元件上,，下調(diào)這些抗凋亡基因的表達(dá),，從而誘導(dǎo)腸癌細(xì)胞凋亡。在小鼠模型中也觀察到敲除TR3基因后,，順鉑對(duì)Apcmin/+小鼠腸道腫瘤或裸鼠移植瘤的抑制效果被明顯地削弱,。
該研究發(fā)現(xiàn)了順鉑通過(guò)TR3介導(dǎo)來(lái)誘導(dǎo)腫瘤細(xì)胞凋亡的新途徑，為腸癌的治療提供了新的藥物靶點(diǎn),。
此外,，今年10月吳喬課題組研究人員在Onocogene雜志上發(fā)表了另一篇研究論文，證實(shí)了Pin1對(duì)TR3異構(gòu)化修飾是TR3發(fā)揮其促細(xì)胞增殖功能的前提,，從而為癌癥治療提供了一個(gè)潛在的新靶點(diǎn),。而在8月發(fā)表于國(guó)際SCI源刊物《GUT》的文章中，揭示了孤兒受體TR3通過(guò)負(fù)調(diào)控Wnt信號(hào)通路活性抑制結(jié)腸癌發(fā)生的分子機(jī)理,。該研究從分子,、細(xì)胞、小鼠和臨床水平證實(shí)了TR3可以作為結(jié)腸癌治療的一個(gè)潛在靶點(diǎn),，TR3激動(dòng)劑則可能成為治療結(jié)腸癌的潛在藥物,。（生物谷Bioon.com）
doi:10.1093/carcin/bgr287
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Orphan receptor TR3 participates in cisplatin-induced apoptosis via Chk2 phosphorylation to repress intestinal tumorigenesis
Lu-ming Yao1, Jian-ping He1, Hang-zi Chen, Yuan Wang, Wei-jia Wang, Rong Wu, Chun-dong Yu and Qiao Wu*
Cisplatin is a widely used antitumor agent that induces aggressive cancer cell death via triggering cellular proteins involved in apoptosis. Here, we demonstrate that cisplatin effectively induces orphan nuclear receptor TR3 phosphorylation by activating Chk2 kinase activity and promoting cross-talk between these two proteins, thereby contributing to the repression of intestinal tumorigenesis via apoptosis. Mechanistic analysis has demonstrated that Chk2-induced phosphorylation enables TR3 to bind to its response elements on the promoters of the BRE and RNF-7 genes, leading to the negative regulation of these two anti-apoptotic genes. Furthermore, the induction of apoptosis by cisplatin is mediated by TR3, and knock-down of TR3 reduces cisplatin-induced apoptosis in colon cancer cells by 27%. The role of TR3 in cisplatin chemotherapy was further clarified in mouse models. In Apcmin/+ mice, cisplatin inhibits intestinal tumorigenesis by 70% in a TR3 phosphorylation-dependent manner; however, the loss of TR3 function in Apcmin/+/TR3-/- mice leads to the failure of cisplatin-induced repression of tumorigenesis. Consistently, xenografts derived from TR3 knock-down colon cancer cells are insensitive to cisplatin treatment, whereas a significant curative effect (50% inhibition) is observed in xenografts with functional TR3. Taken together, our study reveals a novel cross-talk between Chk2 and TR3 and sheds light on the mechanism of cisplatin-induced apoptosis through TR3. Therefore, TR3 may be a new target of cisplatin for colon cancer therapy.
