摘要
血管生成素(Angiogenin, ANG;亦称RNase A family 5)可以特异性地定位于血管内皮细胞及一些肿瘤细胞的细胞核,在血管新生和肿瘤发生中起重要作用,但其具体的作用机制尚未完全明了。microRNA是一类非编码小RNA,通过在转录后水平对基因表达的调控而影响生物学过程,包括血管生成及肿瘤形成等,但目前并不了解其与ANG的关系。为此,本论文从直接受ANG调控的microRNAs和直接靶向调控ANG的microRNAs两个方面研究了ANG特异的microRNAs及其生物学功能。
为探索受ANG影响和调控的microRNAs,本论文首先利用microRNA芯片筛选的方法,在血管内皮细胞中鉴定受ANG刺激后表达发生改变的microRNAs。通过筛选,共得到了26个在ANG刺激前后发生差异表达的microRNAs,包括17个上调和9个下调的microRNAs.生物信息学分析显示,这些microRNAs参与多种生物学过程,包括肿瘤发生和转移、血管生成、神经发育、细胞凋亡等。利用数据库MicroCosm,初步预测了这些microRNAs的靶基因。另一方面,本论文利用ChIP-on-Chip方法探索了ANG与microRNAs启动子区的结合情况,发现有121个microRNAs启动子区可能与ANG结合,其中有9个启动子控制的microRNAs与上述利用microRNA芯片筛选得到的受ANG直接调控的microRNAs相同,包括8个上调和1个下调的microRNAs。在此基础上,利用ChIP-QPCR的方法对所得到的部分microRNA启动子区做进一步验证,发现miR-149、miR-17、miR-378和miR-641等确实受ANG的调控,说明ANG具有转录因子的活性,可以通过结合microRNAs的启动子区而对其表达水平进行调控。
ANG是一个在血管内皮细胞和肿瘤细胞中高表达的蛋白质,本身也可能受到microRNAs的靶向调控。为此,本论文首先通过生物信息学方法预测得到8个可能靶向结合到ANG基因3'UTR的microRNAs,然后分析了它们对ANG mRNA和蛋白质表达水平的影响,发现miR-1208、miR-196b、miR-296、miR-409、miR-570和miR-641共六个microRNAs确实可以调节ANG的表达,并对靶细胞的增殖、迁移、粘附和管腔形成均有一定影响。在此基础上,本论文着重对miR-409进行了较深入的研究,发现miR-409不仅可以抑制内皮细胞的管腔形成和细胞增殖,也可以抑制肿瘤细胞HT1080的增殖及血管拟态；小鼠移植瘤实验也证明了miR-409可以抑制肿瘤的生长、血管生成和转移。进一步,本论文在结肠癌病人的组织中发现miR-409的表达较相应癌旁组织的表达下降,并且miR-409的表达与肿瘤的转移密切相关。以上结果说明ANG本身可以受多种microRNAs的调控,其中miR-409可以直接靶向下调ANG的表达,影响ANG在血管生成及肿瘤发生、发展中的作用。
综合上述两部分的研究结果,说明ANG不仅可以调控microRNAs的表达,而且其本身也同时被多种microRNAs所调控。通过这些microRNAs组成的调控网络,一方面决定了细胞中ANG的表达水平,另一方面也放大了ANG对细胞行为的影响,从而实现其对血管生成和肿瘤发生的促进作用。
Angiogenin (Angiogenin, RNase A family 5) is a critical factor involved in angiogenesis and tumorigenesis. It can translocate to the nucleus of HUVECs and bind to the genomic DNA, but the mechanism of ANG-induced angiogenesis or tumorigenesis is still unclear. MicroRNAs are small non-coding RNAs, which regulate gene expression post-transcriptionally and are considered to play important roles in many biological events, including angiogenesis and tumorigenesis. However, the microRNAs involved in ANG related biological processes have not identified yet. Thus, exploring both the ANG regulated microRNAs and the microRNAs targeting to ANG are two aspects of this thesis to elucidate the ANG-specific microRNAs and their biological functions.
To explore the ANG regulated microRNAs, first we employed a microRNA Chip to screen the ANG-specific or ANG-regulated microRNAs in HUVECs. After ANG stimulation, the expressions of 26 microRNAs were altered in HUVECs, including 17 up-regulated microRNAs and 9 down-regulated microRNAs. The function and the potential targets of these microRNAs were analyzed by a bioinformatics approach. Overall, these microRNAs were reported to involve in many biological processes, including tumorigenesis and metabasis, angiogenesis, neural development, and apoptosis. The potential targets of these microRNAs were predicted with the MicroCosm Database. Furthermore, a ChIP-on-Chip assay was carried out to explore whether ANG can bind to microRNA promoters to regulate the transcription of certain microRNAs. Data showed that 121 microRNA promoters could be potentially bound by ANG,9 of which were identified as ANG regulated microRNAs as well, including 8 up-regulated and 1 down-regulated microRNAs. Partial bindings were validated with a ChIP-QPCR assay, including the ANG bindings to miR-149, miR-17, miR-378, and miR-641 promoter regions, suggesting that ANG could up-regulate their transcriptions as a transcriptional factor.
On the other hand, ANG was reported to be highly expressed in both vessel endothelial cells and tumor cells, suggesting itself might be a regulating target of microRNAs. In order to find the microRNAs targeting to ANG-3'UTR, bioinformatic analysis was employed to predict the potential candidates, and 8 microRNAs were chosen for further validation of their bindings to ANG-3'UTR. Among them, six microRNAs, i.e. miR-1208, miR-196b, miR-296, miR-409, miR-570, and miR-641 could inhibit ANG mRNA and protein expression and show various repression effects on cell proliferation, cell migration, cell adhesion and tubular formation. Especially, miR-409 was found not only to inhibit HUVECs cell proliferation and tubular formation, also inhibit vascular mimicry and cell proliferation of tumor cell HT1080. Furthermore, miR-409 could inhibit tumor growth, angiogenesis and metastasis in in vivo tumor xenografts in nude mice. In addition, the expression of miR-409 in colorectal cancer was lower than the corresponding tumor-adjacent tissues, meanwhile the clinical outcomes of the patients are related with miR-409 expression, expecially tumor metastasis. Thus, ANG could be regulated by different microRNAs, and miR-409 can affect angiogenesis, tumorigenesis and metastasis through negtively regulating ANG expression.
Taken together, ANG can not only regulate the expression of microRNAs, but its own expression is modulated by microRNAs Through a regulatory network consisting of different microRNAs, the functions of ANG are precisely regulated,to exert its role in angiogenesis and tumorigenesis.
引文
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