本文選題：上皮細(xì)胞　切入點(diǎn)：E-cadherin　出處：《吉林大學(xué)》2016年博士論文

【摘要】：上皮細(xì)胞和間質(zhì)細(xì)胞是兩種不同形態(tài)的細(xì)胞。它們具有不同的表型和功能。但是這兩種細(xì)胞形態(tài)均具有可塑性,并且可以在特定條件下相互轉(zhuǎn)換。上皮細(xì)胞能夠被重新編程成為間質(zhì)細(xì)胞,這一過程即被稱為上皮間質(zhì)細(xì)胞轉(zhuǎn)移(epithelial mesenchymal transition,EMT)。EMT是哺乳動(dòng)物體內(nèi)胚胎正常發(fā)育過程中必不可少的生理現(xiàn)象,但是由于其能夠使上皮細(xì)胞獲得遷移與侵襲能力,因此當(dāng)其受到異常調(diào)控時(shí)就會(huì)造成生理紊亂。人體內(nèi)90%以上的上皮細(xì)胞惡性腫瘤轉(zhuǎn)移浸潤均與EMT相關(guān)。目前,大量的體內(nèi)與體外研究均表明,在肺癌、肝癌、結(jié)腸癌、乳腺癌、胰腺癌以及前列腺癌等多種癌癥的局部浸潤轉(zhuǎn)移和繼發(fā)性遠(yuǎn)端轉(zhuǎn)移中,EMT都扮演著重要的角色。因此,EMT發(fā)生與調(diào)控機(jī)制的研究對于尋找上皮細(xì)胞惡性腫瘤浸潤侵襲與轉(zhuǎn)移的靶基因以及發(fā)現(xiàn)新的的治療方法具有重要的意義。細(xì)胞間粘性影響表皮細(xì)胞在正常發(fā)育過程以及癌癥發(fā)展中的增殖以及流動(dòng)性。轉(zhuǎn)錄因子Snail家族是上皮-間質(zhì)細(xì)胞轉(zhuǎn)移(EMT)的核心誘導(dǎo)物,而EMT的調(diào)控機(jī)制極為復(fù)雜,目前\不十分明確。這里我們展示了F-box蛋白FBXO11識別Snail家族,進(jìn)而通過泛素-蛋白酶體系統(tǒng)降解Snail蛋白。在間質(zhì)細(xì)胞中過量表達(dá)FBXO11可以降低Snail蛋白表達(dá)水平以及細(xì)胞侵襲能力。相反地,在上皮癌細(xì)胞中降低內(nèi)源性FBXO11會(huì)引起Snail蛋白水平的累積,EMT以及腫瘤侵襲。在乳腺癌細(xì)胞中,FBXO11是維持雌激素受體(ER)表達(dá)的必要因子。EMT誘導(dǎo)信號能夠下調(diào)FBXO11的表達(dá)水平。在人類癌癥中,高水平的FBXO11與上皮標(biāo)記物以及良性預(yù)后因素表達(dá)相一致。這些結(jié)果都表明FBXO11能夠維持上皮組織狀態(tài),并且抑制癌癥的發(fā)展。FBXO11缺失小鼠導(dǎo)致新生致死,表皮增厚以及Snail蛋白水平在表皮增加,證明了FBXO11是Snail的生理性的泛素連接酶。而且,在線蟲中,FBXO11也與Snail因子相關(guān),Snail同源物的失活或缺失會(huì)抑制FBXO11突變表型。綜上所述,這些發(fā)現(xiàn)都表明FBXO11-Snail調(diào)節(jié)軸在進(jìn)化上高度保守,并且嚴(yán)格而精確地控制惡性上皮腫瘤的發(fā)生與發(fā)展以及哺乳動(dòng)物表皮層的發(fā)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.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R730.2

【相似文獻(xiàn)】

相關(guān)期刊論文 前10條

1 戴愛華;上皮細(xì)胞在體外的轉(zhuǎn)化[J];癌癥;1986年02期

2 黃肇川;錢桐蓀;;尿曲管上皮細(xì)胞的特點(diǎn)和檢查方法[J];上海醫(yī)學(xué)檢驗(yàn)雜志;1989年04期

3 高丹宇,胡秀文,李雁[，

本文編號：1713189