Fbxo11促进转录因子Snail家族泛素化进而影响癌症发展以及表皮发育

发布时间：2018-04-05 04:22

本文选题：上皮细胞　切入点：E-cadherin　出处：《吉林大学》2016年博士论文

【摘要】：上皮细胞和间质细胞是两种不同形态的细胞。它们具有不同的表型和功能。但是这两种细胞形态均具有可塑性,并且可以在特定条件下相互转换。上皮细胞能够被重新编程成为间质细胞,这一过程即被称为上皮间质细胞转移(epithelial mesenchymal transition,EMT)。EMT是哺乳动物体内胚胎正常发育过程中必不可少的生理现象,但是由于其能够使上皮细胞获得迁移与侵袭能力,因此当其受到异常调控时就会造成生理紊乱。人体内90%以上的上皮细胞恶性肿瘤转移浸润均与EMT相关。目前,大量的体内与体外研究均表明,在肺癌、肝癌、结肠癌、乳腺癌、胰腺癌以及前列腺癌等多种癌症的局部浸润转移和继发性远端转移中,EMT都扮演着重要的角色。因此,EMT发生与调控机制的研究对于寻找上皮细胞恶性肿瘤浸润侵袭与转移的靶基因以及发现新的的治疗方法具有重要的意义。细胞间粘性影响表皮细胞在正常发育过程以及癌症发展中的增殖以及流动性。转录因子Snail家族是上皮-间质细胞转移(EMT)的核心诱导物,而EMT的调控机制极为复杂,目前\不十分明确。这里我们展示了F-box蛋白FBXO11识别Snail家族,进而通过泛素-蛋白酶体系统降解Snail蛋白。在间质细胞中过量表达FBXO11可以降低Snail蛋白表达水平以及细胞侵袭能力。相反地,在上皮癌细胞中降低内源性FBXO11会引起Snail蛋白水平的累积,EMT以及肿瘤侵袭。在乳腺癌细胞中,FBXO11是维持雌激素受体(ER)表达的必要因子。EMT诱导信号能够下调FBXO11的表达水平。在人类癌症中,高水平的FBXO11与上皮标记物以及良性预后因素表达相一致。这些结果都表明FBXO11能够维持上皮组织状态,并且抑制癌症的发展。FBXO11缺失小鼠导致新生致死,表皮增厚以及Snail蛋白水平在表皮增加,证明了FBXO11是Snail的生理性的泛素连接酶。而且,在线虫中,FBXO11也与Snail因子相关,Snail同源物的失活或缺失会抑制FBXO11突变表型。综上所述,这些发现都表明FBXO11-Snail调节轴在进化上高度保守,并且严格而精确地控制恶性上皮肿瘤的发生与发展以及哺乳动物表皮层的发育。
[Abstract]:Epithelial cells and interstitial cells are two different types of cells.They have different phenotypes and functions.But both cell forms are plastic and can be converted to each other under certain conditions.Epithelial cells can be reprogrammed into mesenchymal cells. This process is called epithelial mesenchymal transition.EMT is an essential physiological phenomenon during the normal development of mammalian embryos.But because it can make epithelial cells obtain the ability of migration and invasion, it can cause physiological disorder when it is regulated abnormally.More than 90% of epithelial cell malignant tumor metastasis and infiltration are associated with EMT.At present, a large number of in vivo and in vitro studies have shown that EMT plays an important role in the local invasion and metastasis and secondary distal metastasis of various cancers such as lung cancer, liver cancer, colon cancer, breast cancer, pancreatic cancer and prostate cancer.Therefore, the study on the pathogenesis and regulation of EMT is of great significance in finding the target genes for invasion, invasion and metastasis of epithelial cell malignant tumors and in finding new therapeutic methods.Intercellular viscosity affects the proliferation and fluidity of epidermal cells during normal development and cancer development.The transcription factor Snail family is the core inducer of epithelial-mesenchymal cell metastasis (EMT), but the regulatory mechanism of EMT is very complicated.Here we show that F-box protein FBXO11 recognizes the Snail family and then degrades Snail protein through the ubiquitin proteasome system.Overexpression of FBXO11 in mesenchymal cells decreased the expression of Snail protein and the ability of cell invasion.Conversely, the reduction of endogenous FBXO11 in epithelial cancer cells leads to the accumulation of Snail protein levels and tumor invasion.FBXO11 is a necessary factor to maintain the expression of estrogen receptor ER.EMT-induced signal can down-regulate the expression of FBXO11 in breast cancer cells.In human cancer, high levels of FBXO11 are consistent with epithelial markers and benign prognostic factors.These results suggest that FBXO11 can maintain the state of epithelial tissue and inhibit the development of cancer. FBXO11 deficient mice lead to neonatal death, epidermal thickening and the increase of Snail protein level in the epidermis, which suggests that FBXO11 is a physiologic ubiquitin ligase of Snail.Moreover, the inactivation or deletion of FBXO11 homologue associated with Snail factor also inhibited the FBXO11 mutant phenotype.In conclusion, these findings indicate that the FBXO11-Snail regulatory axis is highly conserved in evolution and strictly and accurately controls the occurrence and development of malignant epithelial tumors and the development of mammalian epidermis.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R730.2

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