Hedgehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells.
Hedgehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells.
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DOI：
10.1002/emmm.201100201
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发表时间：
2012-03
影响因子：
11.1
通讯作者：
Aberger, Fritz
中科院分区：
文献类型：
--
作者：
Eberl, Markus;Klingler, Stefan;Mangelberger, Doris;Loipetzberger, Andrea;Damhofer, Helene;Zoidl, Kerstin;Schnidar, Harald;Hache, Hendrik;Bauer, Hans-Christian;Solca, Flavio;Hauser-Kronberger, Cornelia;Ermilov, Alexandre N.;Verhaegen, Monique E.;Bichakjian, Christopher K.;Dlugosz, Andrzej A.;Nietfeld, Wilfried;Sibilia, Maria;Lehrach, Hans;Wierling, Christoph;Aberger, Fritz
抑制Hedgehog (HH)/GLI信号在癌症中是一种很有前途的治疗方法。HH/GLI与其他致癌途径的相互作用影响HH/GLI的强度和致瘤性。HH/GLI与表皮生长因子受体（EGFR）信号的协同作用促进癌细胞的体外转化和增殖。然而，HH-EGFR信号整合的体内相关性和关键的下游介质在很大程度上是不确定的。在本报告中，我们发现EGFR信号的遗传和药理学抑制可降低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协同应答基因，包括SOX2、SOX9、JUN、CXCR4和FGF19，它们被HH-EGFR信号整合协同激活，是BCC细胞和肿瘤启动性胰腺癌细胞在体内生长所必需的。这些数据验证了EGFR信号在HH/GLI驱动的癌症中作为药物靶点，并揭示了HH-EGFR信号合作控制的分子过程，提供了基于HH-EGFR信号和选择的下游靶基因联合靶向的新治疗策略。
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.
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影响因子：
29.4
作者：
Mueller, Maria-Theresa;Hermann, Patrick C.;Heeschen, Christopher
通讯作者：
Heeschen, Christopher
影响因子：
14.9
作者：
Indra, AK;Warot, X;Metzger, D
通讯作者：
Metzger, D
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Altaba, ARI
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Hui CC
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通讯作者：
Simeone, Diane M.