Epidermal growth factor receptor signaling synergizes with Hedgehog/GLI in oncogenic transformation via activation of the MEK/ERK/JUN pathway.
Epidermal growth factor receptor signaling synergizes with Hedgehog/GLI in oncogenic transformation via activation of the MEK/ERK/JUN pathway.
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DOI：
10.1158/0008-5472.can-08-2331
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发表时间：
2009-02-15
期刊：
影响因子：
11.2
通讯作者：
Aberger F
中科院分区：
文献类型：
--
作者：
Schnidar H;Eberl M;Klingler S;Mangelberger D;Kasper M;Hauser-Kronberger C;Regl G;Kroismayr R;Moriggl R;Sibilia M;Aberger F
Hedgehog（HH）/GLI信号通路的持续激活与许多人类癌症的发展有关。GLI锌指转录因子在HH信号级联的末端起作用以控制基因表达，并且最近的研究已经表明，GLI蛋白的活性可以通过不同信号的整合而另外修饰，所述不同信号例如MEK/细胞外信号调节激酶（ERK）和磷脂酰肌醇-3激酶（PI 3 K）/AKT途径。然而，很少有人知道这些HH/GLI相互作用的信号通路在癌症中的上游激活剂的身份。在这里，我们提供的证据表明，HH/GLI和表皮生长因子受体（EGFR）途径的整合协同诱导致癌转化，这取决于EGFR介导的RAS/RAF/MEK/ERK激活，但不是PI 3 K/AKT途径。EGFR/MEK/ERK信号传导诱导JUN/激活蛋白1激活，这是致癌转化所必需的，与GLI激活剂形式GLI 1和GLI 2组合。此外，EGFR和HH/GLI的药理学抑制有效地减少了源自具有活化的HH/GLI信号传导的小鼠的基底细胞癌（BCC）细胞系的生长。结果确定GLI激活剂功能和EGFR信号传导的协同整合是致癌转化的关键步骤，并为依赖于BCC中HH/GLI和EGFR/MEK/ERK/JUN通路的联合抑制的治疗机会提供了分子基础。
Persistent activation of the Hedgehog (HH)/GLI signaling pathway has been implicated in the development of a number of human cancers. The GLI zinc finger transcription factors act at the end of the HH signaling cascade to control gene expression, and recent studies have shown that the activity of GLI proteins can be additionally modified by integration of distinct signals, such as the MEK/extracellular signal-regulated kinase (ERK) and phosphinositide-3 kinase (PI3K)/AKT pathway. However, little is known about the identity of the upstream activators of these HH/GLI interacting signaling pathways in cancer. Here, we provide evidence that integration of the HH/GLI and epidermal growth factor receptor (EGFR) pathway synergistically induces oncogenic transformation, which depends on EGFR-mediated activation of the RAS/RAF/MEK/ERK but not of the PI3K/AKT pathway. EGFR/MEK/ERK signaling induces JUN/activator protein 1 activation, which is essential for oncogenic transformation, in combination with the GLI activator forms GLI1 and GLI2. Furthermore, pharmacologic inhibition of EGFR and HH/GLI efficiently reduces growth of basal cell carcinoma (BCC) cell lines derived from mice with activated HH/GLI signaling. The results identify the synergistic integration of GLI activator function and EGFR signaling as a critical step in oncogenic transformation and provide a molecular basis for therapeutic opportunities relying on combined inhibition of the HH/GLI and EGFR/MEK/ERK/JUN pathway in BCC.