Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
EMBO Mol Med. 2012 Mar;4(3):218-33. doi: 10.1002/emmm.201100201. Epub 2012 Feb 1.
Inhibition of Hedgehog (HH)/GLI signalling in cancer is a promising therapeutic approach. Interactions between HH/GLI and other oncogenic pathways affect the strength and tumourigenicity of HH/GLI. Cooperation of HH/GLI with epidermal growth factor receptor (EGFR) signalling promotes transformation and cancer cell proliferation in vitro. However, the in vivo relevance of HH-EGFR signal integration and the critical downstream mediators are largely undefined. In this report we show that genetic and pharmacologic inhibition of EGFR signalling reduces tumour growth in mouse models of HH/GLI driven basal cell carcinoma (BCC). We describe HH-EGFR cooperation response genes including SOX2, SOX9, JUN, CXCR4 and FGF19 that are synergistically activated by HH-EGFR signal integration and required for in vivo growth of BCC cells and tumour-initiating pancreatic cancer cells. The data validate EGFR signalling as drug target in HH/GLI driven cancers and shed light on the molecular processes controlled by HH-EGFR signal cooperation, providing new therapeutic strategies based on combined targeting of HH-EGFR signalling and selected downstream target genes.
抑制 Hedgehog（HH）/GLI 信号通路在癌症治疗中具有广阔的应用前景。HH/GLI 与其他致癌途径之间的相互作用影响 HH/GLI 的强度和致瘤性。HH/GLI 与表皮生长因子受体（EGFR）信号通路的协同作用促进了体外转化和癌细胞增殖。然而，HH-EGFR 信号整合的体内相关性及其关键下游介质在很大程度上尚未确定。在本报告中，我们表明，EGFR 信号通路的遗传和药理学抑制可减少 HH/GLI 驱动的基底细胞癌（BCC）小鼠模型中的肿瘤生长。我们描述了 HH-EGFR 合作反应基因，包括 SOX2、SOX9、JUN、CXCR4 和 FGF19，它们被 HH-EGFR 信号整合协同激活，是 BCC 细胞和肿瘤起始性胰腺癌细胞体内生长所必需的。这些数据验证了 EGFR 信号通路作为 HH/GLI 驱动的癌症的药物靶点，并阐明了由 HH-EGFR 信号协同作用控制的分子过程，为基于 HH-EGFR 信号和选定的下游靶基因联合靶向的新治疗策略提供了依据。
