【摘要】：中心體的過度復(fù)制是腫瘤細(xì)胞的典型特征之一。然而,引起中心體過度復(fù)制的原因仍未研究透徹。在生理和病理學(xué)領(lǐng)域,轉(zhuǎn)錄因子KLF家族的功能已經(jīng)被廣泛研究。近年來,KLF14作為脂代謝的重要調(diào)控者已經(jīng)引起了廣泛關(guān)注,但是其真正的生理學(xué)功能仍需大量、深入的研究。在本論文中,我們構(gòu)建了KLF14基因敲除的小鼠,并發(fā)現(xiàn)KLF14的缺失會(huì)導(dǎo)致中心體的過度復(fù)制、基因組的不穩(wěn)定性和自發(fā)腫瘤的產(chǎn)生。分子水平上,我們發(fā)現(xiàn)KLF14能轉(zhuǎn)錄抑制PLK4。PLK4是中心體復(fù)制的主要調(diào)控因子,對(duì)中心粒復(fù)制的起始以及新中心粒的組裝至關(guān)重要。瞬時(shí)基因沉默KLF14會(huì)導(dǎo)致PLK4轉(zhuǎn)錄水平和蛋白水平都上升。而且,KLF14的缺失會(huì)導(dǎo)致AOM/DSS誘導(dǎo)的結(jié)腸癌惡化程度更高。這些結(jié)果表明KLF14的缺失會(huì)引起PLK4表達(dá)上升,促進(jìn)中心體復(fù)制,并最終導(dǎo)致自發(fā)腫瘤的產(chǎn)生。目前對(duì)“中心體過度復(fù)制和基因組不穩(wěn)定性是腫瘤發(fā)生的重要原因之一”這一論點(diǎn)仍存在爭(zhēng)議。我們的研究則支持了這一論點(diǎn)。綜上所述,我們的研究證實(shí)轉(zhuǎn)錄因子KLF14是一個(gè)重要的腫瘤抑制因子,為腫瘤藥物的開發(fā)提供了新的思路。
[Abstract]:Excessive replication of centrosome is one of the typical characteristics of tumor cells. However, the causes of excessive centrosome replication have not been thoroughly studied. The function of transcription factor KLF family has been widely studied in physiology and pathology. In recent years, KLF14 as an important regulator of lipid metabolism has attracted extensive attention, but its true physiological function still needs a lot of in-depth research. In this paper, we constructed KLF14 knockout mice and found that the deletion of KLF14 leads to excessive replication of centrosome, genomic instability and spontaneous tumor production. At the molecular level, we found that KLF14 transcriptional inhibition of PLK4.PLK4 is the main regulatory factor for centrosomal replication, which is very important for the initiation of centroid replication and the assembly of new centroids. Transient gene silencing of KLF14 results in an increase in PLK4 transcription and protein levels. Moreover, loss of KLF14 can lead to a higher degree of deterioration of colon cancer induced by AOM/DSS. These results suggest that the deletion of KLF14 can induce the increase of PLK4 expression, promote centrosomal replication, and eventually lead to spontaneous tumor. The argument that centrosomal overreplication and genomic instability are one of the major causes of tumorigenesis is still controversial. Our research supports this argument. In conclusion, our study confirmed that transcription factor KLF14 is an important tumor suppressor, which provides a new idea for the development of tumor drugs.
【學(xué)位授予單位】：華東師范大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R730.2

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