建立並分析乳癌中微小核糖核酸與基因間表現量調控網路

Abstract

乳癌是全世界女性癌症最常見的癌症，死亡率全球第五，容易併發癡呆症、心肺功能疾病、糖尿病等疾病。近年研究發現微小核醣核酸 (miRNA) 與許多疾病和癌症有關， 例如肝癌、肺癌、腸癌、糖尿病等，且可能可以當作生物標記和標靶治療的關鍵。miRNA是長度約為19-24個核苷酸 的非編碼小RNA分子，其功能為在轉錄後修飾時藉由抑制基因表現而改變基因對許多疾病和癌症的控制。本研究以探討miRNA調控乳癌相關分子機制為主要研究動機。本研究先從癌症基因圖譜 (TCGA) 資料庫中找出89個正常和161個TNBC、592個Luminal A、147個Luminal B、40個HER2 +腫瘤患者，藉分析找出表現量有差異的miRNAs與基因。分析結果共找出43個miRNA與1776個基因。為了進一步研究miRNA在乳癌中所扮演的角色，找出乳癌的miRNA與基因間調控網路是必要的。使用實驗驗證的轉錄因子與miRNA (TF-miRNA) 資料庫TransmiR找出乳癌中TF-miRNA之間調控關係，再利用實驗驗證的miRNA-target交互作用資料庫miRTarBase找出乳癌中miRNA-target之間的關係，另外通過四種miRNA-target預測工具miRanda，TargetScan，PITA和RNAhybrid預測出可能的miRNA-target。綜合上述結果，最後共找出了14個上調的miRNA和40個下調的target mRNA和9個下調的miRNA和19個上調的target mRNA。從完成的資料中得出上調的miR-21-5p與下調的miR-145-5p在4種類型中都有出現且調控基因數都最多，從結果推斷miR-21-5p調控TGFBR2、TGFBR3、TP63在乳癌中扮演重要的調控角色。

Breast cancer is the second most common cause of cancer deaths. Traditional therapeutic strategies for individual patients are guided by the expression status of the estrogen and progesterone receptors (ER and PR) and human epidermal growth factor receptors (HER2). MicroRNAs (miRNAs), a class of non-coding RNAs (ncRNAs) with 19-24 nucleotides length, regulate multiple biological processes including proliferation, cell death, development, genome and epithelial-mesenchymal transition (EMT). In addition, previous studies reported that miRNAs play an important role in cancer progression. Thus, we are interested to find candidates of miRNAs within breast cancer via The Cancer Genome Atlas (TCGA) first and then to experimentally validate biological functions of miRNA-mRNA in human breast cancer cell lines. Than integrated analysis of microRNA and mRNA expression were from (TCGA) datasets. Using expression profiles that have 89 normal and 161 breast cancer, 592 Luminal A, 147 Luminal B, 40 HER2+ tumor patients were found differentially expressed mRNAs and microRNAs. Bioinformatics analysis identified 43 microRNAs and 1776 mRNAs that were differentially expressed. Correlations between microRNAs expression and mRNA expression were applied and retained microRNAs and mRNAs target relationships which were predicted by four prediction tools miRanda, TargetScan, PITA and RNAhybrid. The microRNA-mRNA pairs combined by 14 up-regulated microRNAs and 40 down-regulated target mRNAs and 9 down-regulated microRNAs and 19 up-regulated target mRNAs were identified. From this study we find miR-21-5p and miR-145-5p regulating great amount gene, especially miR-21-5p target TGFBR2, TGFBR3, TP63 play import role in breast cancer.