乳腺癌中hsa-miR-17-92基因簇及其旁系同源体的共调控作用

Regulation Function of hsa-miR-17-92 Cluster and Two Paralogs in Breast Cancer

hsa-miR-17-92基因簇高度保守,可以作为抑癌基因抑制乳腺癌细胞的增殖.包括2个旁系同源体:miR-106a-363和miR-106b-25基因簇,其序列高度相似,可能通过调控共同靶基因而具有相似的功能.探讨3个基因簇转录的15条microRNA的序列特征,以及共调控靶基因在人类乳腺正常和癌细胞系中的表达;并进一步就显著差异表达基因进行GO和Pathway(KEGG)分析.结果表明,超过75%(178/236)的共调控靶基因表达具有显著差异性,这些基因可能与生物体的细胞代谢、转录后调控、生物合成等多种生物学过程有关,参与细胞周期,癌症等信号通路.分析发现乳腺特异基因PTPN4在乳腺癌中的低表达影响蛋白磷酸化水平和细胞周期,SMAD4、CCND1和E2F1作为与细胞周期相关基因在细胞的G1期起重要作用,它们的低表达阻止细胞从G1期进入S期,从而抑制癌细胞的生长,起到抑癌作用.特别是,一方面基因簇调控CCND1和E2F1使其低表达,另一方面它们作为转录因子结合到基因簇的启动子区诱导基因簇表达,从而形成负反馈调控循环调控下游基因表达.

hsa-miR-17-92 cluster is a highly conserved gene cluster,and can be used as a tumor suppressor gene to inhibit breast cancer cell proliferation.It has two paralog clusters,miR-106a-363 cluster and miR-106b-25 cluster.And they maybe have similar functions,because they have same target genes.The features of 15 microRNA primary sequences and the gene expression profiles of target genes together regulated by three clusters in tumor and normal breasts are analyzed.Then,by Gene Ontology（GO）and Pathway（KEGG）analysis of these significant difference genes,the results indicate that more than 75% target genes display significant difference expressions,and these significant difference target genes have great relevance with cellular metabolism,post-transcriptional regulation,biosynthesis,etc.and may involve in cell cycle and the pathway of cancer.By further analysis,It is found that the lower expression of breast cancer specific gene PTPN4 can affect the protein phosphorylation and cell cycle.And SMAD4,CCND1 and E2F1as cell cycle genes play an important role in G1 stage,their lower expressions maybe prevent cells from G1 stage change into S stage,and inhibit the growth of breast cancer cells.The microRNA＇s target genes CCND1 and E2F-1can combine to the promoter region of microRNA cluster and form a feed-back network with microRNA,and then regulate downstream genes in breast cancer.