Transcription factor HMGA2 controls the K-RAS mediated transformation-specific genetic program

(HMGA2). To elucidate the role of HMGA2 in the transcriptional network affected by oncogenic signaling, we used an integrated approach combining RNAi-mediated silencing, microarray-based expression profiling, computational prediction of transcription factor binding sites in target gene promoters and phenotypic analysis. Knocking-down HMGA2 resulted in the reversion of epithelial-mesenchymal transition, loss of anchorage independence and in a substantial restoration of the gene expression pattern characteristic of non-transformed ROSE cells. Computational prediction of transcription factor binding sites in the promoters of HMGA2-regulated genes and expression profiling revealed a preferential role of activator complex-1 (AP-1) components Fra-1 and JunB in target gene regulation. Forced expression of HMGA2 did not transform normal ovarian epithelial cells, suggesting that HMGA2 up-regulation is not sufficient for inducing the transformed phenotype, but mediates cancer-specific phenotypic traits in cells expressing mutated KRAS and, hence, oncogene addiction.(HMGA2)。为阐明HMGA2在致癌信号通路调控的转录网络中的作用，本研究采用整合研究策略，结合RNA干扰（RNA interference, RNAi）介导的基因沉默、基于微阵列的表达谱分析、靶基因启动子区域转录因子结合位点的计算预测，以及表型分析。敲低HMGA2可逆转上皮间质转化（epithelial-mesenchymal transition, EMT），使细胞丧失锚定非依赖性生长能力，并显著恢复非转化ROSE细胞特有的基因表达模式。对HMGA2调控基因的启动子区域进行转录因子结合位点的计算预测，并结合表达谱分析结果显示，激活蛋白复合物-1（activator complex-1, AP-1）组分Fra-1与JunB在靶基因调控中发挥优先作用。强制过表达HMGA2并不会转化正常卵巢上皮细胞，这表明HMGA2的上调不足以诱导细胞产生转化表型，但可在携带突变KRAS的细胞中介导癌症特异性表型特征，进而引发癌基因成瘾现象。