TIAM1基因与大肠癌EMT的相关性及其相关miRNA的生物信息学分析

Bioinformatics analysis on relationship between TIAM1 gene and epithelial-mesenchymal transition of colorectal cancer and 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。综合两种分析，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microRNA hsa-mir-340 最可能能够与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TGF-β受体、雄激素受体、NF-kB、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-kB、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 using miRNA predicting tools ,next analyzed the miRNA which related with the deletion of TIAM1 by using the expression profiles of colorectal cancer cell lines SW480 with deleted TIAM1; then selected the miRNA (hsa-mir-340) which related with TIAM1 from the above two analyses. We forecasted target genes of the miRNA and doing pathway enrichment analysis. We compared the enrichment results and TIAM1 interaction protein pathway enrichment result.We did the pathway enrichment for the gene set whose expression profile logarithmic ratio was greater than 1 compared with that of wild type sw480 cell lines.We did the pathway enrichment using the protein which in protein-protein interaction network of TIAM1.We then did the pathway enrichment for the protein which interacted with TIAM1 directly and indirectly to epithelial mesenchymal transition (EMT) markers named E-cadhrin and Vimentin. Results: All of the direct prediction and indirect prediction show that microRNA hsa-mir-340 can interact with TIAM1 and coordinate with TIAM1 on the function seen from the pathway enrichment result.We analyzed the expression data of the SW480 which deleted the TIAM1 and clarified that the lack of the TIAM1 is related to the over-active of the P53 signal pathway,DNA damage response,Toll-like receptor signal pathway and so on.That means the lack of the TIAM1 may related to the enhance the antitumor effect.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. These signaling pathways were possibly related with the phenomenon of the EMT in colorectal cancer. Conclusions: hsa-mir-340 can regulate the expressions of TIAM1.Signal 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 signal pathways such as TGF-β receptor、androgen receptor、NF-kB、MAPK.