【作者】 吴华；

【导师】 张晓坤； 曾锦章；

【作者基本信息】 厦门大学 ， 细胞生物学， 2009， 硕士

【摘要】 视黄醇(retinoids)是天然的或人工合成的维生素A衍生物,在细胞的生长、分化以及凋亡中发挥着重要的作用。许多视黄醇类似物已经被开发成新的抗癌药物,并在临床上广泛应用于癌症的治疗。视黄醇的生物学作用由视黄酸受体(Retinoic acid receptor,RAR)和视黄醇X受体(Retinoid X receptor,RXR)两类核受体所介导,这两类受体分别由α、β和γ三种不同的基因所编码,这些基因在进化上高度保守,但它们在胚胎发育调控过程中以及成年组织中的表达分布却不尽相同,说明不同受体具有各自独特的功能。在本研究中,我们发现RARγ在不同的细胞和不同组织的表达水平有较大的差异,在肝癌组织中,我们发现该基因普遍高表达,在肝癌细胞HepG2的体外实验中,我们发现RARγ可以与p85α相互作用,从而激活PI3K/AKT信号通路,诱导IκBα磷酸化和p65向核内转位,激活NF-κB转录功能,并最终诱导AFP蛋白的表达。结果表明,RARγ在肝癌中的表达有可能介导炎症发生和促进癌细胞增殖,提示了RARγ有可能成为开发抗肝癌药物的一个有效的分子靶点。针对这样的分子机制,我们从天然产物中筛选到了一种黄酮类化合物——刺槐黄素,发现它能够通过诱导RARγ的降解来抑制AKT的磷酸化及肝癌细胞的生长。更多还原

【Abstract】 Retinoids,a group of natural or synthetic vitamin A derivatives,play an important role in the regulation of cell proliferation,differentiation and apoptosis. Some of these compounds have been developed as effective anticancer drugs.The biological actions of retinoids are primarily mediated through two classes of nuclear receptors,retinoic acid receptors(RARs) and retinoid X receptors(RXRs). Both RAR and RXR are encoded by three distinct genes,α,β,andγ,which are highly conserved amongst species and spatiotemporally expressed in developing embryos and adult tissues.Their distinct distributions suggest that individual isotypes may have unique and specific function.In this study,we show that the expression level of RARγvaries among different tissues and that it is frequently overexpressed in liver tumors.Using in vitro cell culture system,we find that RARγupon binding to its ligand all-trans-retinoic acid (ATRA) interacts with the p85αregulatory subunit of the phosphoinositide 3-kinase (PI3K),leading to activation of PI3K and its downstream target AKT.The activation of PI3K/AKT signaling is accompanied with phosphorylation and degradation of inhibitor ofκBα(IκBα),which then stimulates nuclear translocation of p65/RelA and and NF-κB transcriptional activity.Based on our mechanistic studies,we have also screened a natural products library for antagonizing the RARγ-mediated NF-κB pathway and successfully identified a flavonoid derivative Acacetin that can induce RARγdegradation and inhibition of RARγ-mediated activation of PI3K/AKT/NF-κB signaling.Together,our results demonstrate that RARγfunctions to induce inflammation of liver cancer cells and their growth by nongenomically activating the PI3K/AKT/NF-κB pathway,suggesting that it may represents an attractive molecular target for developing anti-liver cancer agents.Our results also suggest that Acacetin is a promising lead for developing new agents for treating liver cancer.更多还原