Ben May Department for Cancer Research, University of Chicago, IL, USA.
EMBO J. 2011 Aug 26;30(21):4500-14. doi: 10.1038/emboj.2011.312.
Tumour metastasis suppressors are inhibitors of metastasis but their mechanisms of action are generally not understood. We previously showed that the suppressor Raf kinase inhibitory protein (RKIP) inhibits breast tumour metastasis in part via let-7. Here, we demonstrate an integrated approach combining statistical analysis of breast tumour gene expression data and experimental validation to extend the signalling pathway for RKIP. We show that RKIP inhibits let-7 targets (HMGA2, BACH1) that in turn upregulate bone metastasis genes (MMP1, OPN, CXCR4). Our results reveal BACH1 as a novel let-7-regulated transcription factor that induces matrix metalloproteinase1 (MMP1) expression and promotes metastasis. An RKIP pathway metastasis signature (designated RPMS) derived from the complete signalling cascade predicts high metastatic risk better than the individual genes. These results highlight a powerful approach for identifying signalling pathways downstream of a key metastasis suppressor and indicate that analysis of genes in the context of their signalling environment is critical for understanding their predictive and therapeutic potential.
肿瘤转移抑制因子是转移的抑制剂，但它们的作用机制通常不为人知。我们之前曾表明，抑制丝裂原活化蛋白激酶激酶抑制蛋白（RKIP）通过 let-7 在一定程度上抑制乳腺癌转移。在这里，我们采用了一种综合的方法，结合乳腺癌肿瘤基因表达数据的统计分析和实验验证，扩展了 RKIP 的信号通路。我们表明 RKIP 抑制了 let-7 的靶标（HMGA2、BACH1），而 let-7 的靶标又反过来上调了骨转移基因（MMP1、OPN、CXCR4）。我们的结果揭示了 BACH1 是一种新的 let-7 调控的转录因子，它诱导基质金属蛋白酶 1（MMP1）的表达并促进转移。源自完整信号级联的 RKIP 通路转移特征（指定为 RPMS）比单个基因更好地预测高转移风险。这些结果突出了一种识别关键转移抑制因子下游信号通路的有效方法，并表明在信号环境中分析基因对于理解它们的预测和治疗潜力至关重要。
