采用系统生物学方法分析乳腺癌转移中Runx2对细胞外基质重塑的调节机制

Analysis of the Mechanism of Runx2 in Regulating Extracellular Matrix Remodeling in Breast Cancer Metastasis via Systems Biology

摘要细胞外基质(extracellular matrix,ECM)重塑是癌细胞迁移的关键步骤.本研究基于乳腺癌组织的基因表达谱数据,采用系统生物学方法推测乳腺癌转移中Runx2对细胞外基质重塑的调节机制.采用相关性分析程序分析49例乳腺原发癌和15例淋巴结转移癌组织的基因表达谱数据,筛选与Runx2呈相关性表达的基因,结果得到与ECM重塑相关的候选基因52个,包括ECM成分11个,ECM降解酶及其抑制剂8个,细胞信号分子33个.利用转录调节因子结合序列数据库搜索候选基因启动子区的Runx2结合模序,筛选其中Runx2转录调控的ECM重塑相关基因,并判断可能调节Runx2的上游信号分子;文献检索实验证实的与Runx2有相互调节关系的基因,并基于Runx2上游调控信号分子和下游转录调节基因的分析,构建得到以Runx2为中心的ECM重塑的生物学调控网络.WNT和TGF/BMPs是启动Runx2表达的主要信号通路,Runx2通过转录调节ECM组分、ECM降解酶及其抑制剂和信号分子调节ECM重塑,促进癌细胞完成转移的生物学过程.

Extracellular matrix（ECM）remodeling plays a key role in cancer metastasis. The purpose of this study was to elucidate the mechanism of Runx2 in regulating ECM remodeling in the process of breast cancer metastasis using systems biology method based on previous expression profiling data. Fifty two candidate genes related to Runx2 were screened by analyzing their correlation based on the expression profiling data of 49 primary breast cancers and 15 lymph node metastases,including 11 ECM components, 8 degrading enzymes of ECM and their inhibitors,and 33 signal molecules. Thirty-three genes were identified as candidate genes regulated by Runx2 with one or more Runx2 binding sequence in their promoters and the other 19 genes were identified as upstream regulating genes of Runx2 without Runx2 binding sequence in their promoters in a transcription regulatory factor binding sequence database. Furthermore,the correlation of Runx2 and 11 genes have been proved by experiments in published papers. A Runx2-centered biologic network in regulating ECM remolding was conceived based on the analysis of upstream regulating genes of Runx2 and candidate genes regulated by Runx2. WNT and TGF / BMPs are the main signal pathways initiating Runx2 expression,and Runx2 can regulate the ECM remodeling and promote the metastasis by changing the expression level of ECM components,degrading enzymes of ECM and their inhibitors,and cell signal molecules.