TIAM1基因与大肠癌上皮间质转化的相关性及其相关miRNA的生物信息学分析

Relationship between TIAM1 gene and epithelial-mesenchymal transition of colorectal cancer and bioinformatics analysis of TIAM1 gene related-miRNA

摘要:

目的：对TIAM1基因进行生物信息学分析，探讨TIAM1基因在大肠癌细胞中的生物学功能及其在细胞信号网络中的作用。方法：通过miRNA预测工具预测与TIAM1相互作用的miRNA，通过TIAM1基因敲除的大肠癌细胞株SW480表达谱数据分析与TIAM1基因缺失相关的miRNA。综合2种分析，挑选出最可能与TIAM1相关的miRNA。预测此miRNA的靶基因，并对靶基因进行通路富集，富集结果与TIAM1相互作用蛋白通路富集结果进行比较。将TIAM1缺失的SW480表达谱数据比野生型SW480表达谱数据中对数比大于1的基因集进行通路富集。对TIAM1相互作用蛋白网络中的蛋白进行通路富集。对TIAM1间接作用于上皮间质转化（epithelial mesenchymal transition，EMT）标志物E-cadherin和Vimentin的中间传递蛋白进行通路富集。结果：直接预测与间接预测均表明miRNA hsa-mir-340最可能与TIAM1相互作用，通过通路富集结果的比较也发现hsa-mir-340功能上与TIAM1协同。对TIAM1缺失的SW480表达谱数据分析发现，TIAM1缺失后P53信号通路、DNA损伤的应答反应、Toll样受体信号通路等表达上调，表明TIAM1缺失可能与抑瘤作用增强相关。对TIAM1相互作用蛋白的通路富集可以发现TIAM1相互作用蛋白参与了细胞黏附、细胞骨架重构、细胞增殖与生长等信号通路，与肿瘤的发生发展密切相关。对TIAM1与EMT标志物E-cadherin和Ｖimentin的中间传递蛋白分析发现其主要由转化生长因子－?茁（transforming growth factor-?茁，TGF-β）受体、雄激素受体、核因子－?资B（nuclear factor-?资B，NF-?资B）、丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）等信号通路的成员构成。说明这些信号通路可能与TIAM1促进大肠癌EMT的发生相关。结论：预测hsa-mir-340能够调控TIAM1的表达，TIAM1的缺失可能导致抑瘤作用增强，TIAM1相互作用蛋白与肿瘤的转移密切相关。TIAM1可能通过TGF-β受体、雄激素受体、NF-?资B、MAPK等信号通路影响EMT标志物E-cadherin和Ｖimentin的功能，进而促进大肠癌EMT的发生和转移。

Abstract:

Objective：To explore the biological function of TIAM1 gene in colorectal cancer cells and its role in cell signaling network by doing bioinformatics analysis. Methods：Firstly，we forecasted the miRNA which interacted with TIAM1 by miRNA predicting tools；then analyzed the miRNA which related with the deletion of TIAM1 by expression profiles of colorectal cancer cell lines SW480 with deleted TIAM1；then selected the miRNA most possibly related with TIAM1 by synthesizing the intersection of the above two analyses. We clarified the signaling pathway participated by these target genes by predicting the target genes of hsa-mir-340 and doing pathway enrichment analysis. We made comparison between enrichment analysis results of target genes and results of proteins related with TIAM1. We clarified the signaling pathway situation which related with the deletion of TIAM1 by selecting the genes in sw480 cell lines with deleted TIAM1，whose expression profile logarithmic ratio was greater than 1 compared with that of wild type sw480 cell lines，and by analyzing the pathway enrichment of these genes. We analyzed the pathway enrichment for the protein in the protein-protein interaction network of TIAM1. We then analyzed the pathway enrichment for the protein which interacted with TIAM1 di－rectly and indirectly to epithelial mesenchymal transition（EMT） markers named E-cadherin and Vimentin. Results：Direct and indi－rect forecast demosnterated that microRNA hsa-mir-340 can interact with TIAM1 and coordinate with TIAM1 on the func－tion. Based on the analysis of SW480 with deleted TIAM1，ex－pressions of P53 signal pathway，DNA damage response，and Toll-like receptor signal pathway were up-regulated，indicating deleted TIAM1 may correlated with tumor inhibitory. According to the pathway analysis results，TIAM1 gene participated in a lot of signaling pathways such as the cell adhesion，cytoskeleton remodeling，cell proliferation and growth，etc and was possibly related with cancer development. TIAM1 and EMT markers E-cadherin and Vimentin regulatory network proteins were the signaling pathway members of transforming growth factor-β（TGF-β） receptor，androgen recep－tor，nuclear factor-?资B（NF-?资B），mitogen-activated protein kinase（MAPK），etc. These signaling pathways were possibly related with the occurrence of the EMT of colorectal cancer. Conclusions：Predicting hsa-mir-340 can regulate the expressions of TIAM1. TIAM1 deletion may correlate with tumor inhibitory and signaling pathway related with TIAM1 has close relationship with cancer metastasis. TIAM1 can influence the function of EMT markers E-cadherin and Vimentin and promote the colorectal cancer occurrence and metastasis by affecting EMT signaling pathways such as TGF-β receptor，androgen receptor，NF-kB，MAPK.