Aberrantly activated AREG-EGFR signaling is required for the growth and survival of CRTC1-MAML2 fusion-positive mucoepidermoid carcinoma cells
Aberrantly activated AREG-EGFR signaling is required for the growth and survival of CRTC1-MAML2 fusion-positive mucoepidermoid carcinoma cells
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DOI：
10.1038/onc.2013.348
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发表时间：
2014-07-17
期刊：
影响因子：
8
通讯作者：
Wu, L.
中科院分区：
文献类型：
--
作者：
Chen, Z.;Chen, J.;Wu, L.
涎腺肿瘤（SGT）是一组高度异质性的头颈部恶性肿瘤，临床结果差异很大，没有标准有效的治疗方法。CRTC1-MAML2融合癌基因由复发性染色体易位t(11; 19)（q14-21; p12-13）编码，是在最常见的恶性sgt黏液表皮样癌（MEC）中发现的一种常见的遗传改变。在本研究中，我们旨在确定CRTC1-MAML2癌基因在维持MEC肿瘤生长中的作用，并研究MEC治疗靶向的关键下游靶基因和途径。通过RNA干扰和药理学调节进行基因表达分析和功能研究，我们确定了CRTC1-MAML2融合基因及其下游AREG-EGFR信号在人MEC异种移植模型中体外和体内人MEC癌细胞生长和存活中的重要性。我们发现CRTC1-MAML2融合癌基因是融合阳性的人MEC癌细胞在体外和体内生长和存活所必需的。CRTC1-MAML2癌蛋白通过共激活转录因子CREB诱导表皮生长因子受体（EGFR）配体双调节蛋白（AREG）的上调，AREG随后以自分泌方式激活EGFR信号，促进MEC细胞的生长和存活。重要的是，crtc1 - maml2阳性的MEC细胞对EGFR信号抑制高度敏感。因此，我们的研究表明，异常激活的AREG-EGFR信号是crtc1 - maml2阳性MEC细胞生长和存活所必需的，这表明egfr靶向治疗将使晚期、不可切除的crtc1 - maml2阳性MEC患者受益。
Salivary gland tumors (SGT) are a group of highly heterogeneous head and neck malignancies with widely varied clinical outcomes and no standard effective treatments. The CRTC1-MAML2 fusion oncogene, encoded by a recurring chromosomal translocation t(11; 19)(q14-21; p12-13), is a frequent genetic alteration found in > 50% of mucoepidermoid carcinomas (MEC), the most common malignant SGT. In this study, we aimed to define the role of the CRTC1-MAML2 oncogene in the maintenance of MEC tumor growth and to investigate critical downstream target genes and pathways for therapeutic targeting of MEC. By performing gene expression analyses and functional studies via RNA interference and pharmacological modulation, we determined the importance of the CRTC1-MAML2 fusion gene and its downstream AREG-EGFR signaling in human MEC cancer cell growth and survival in vitro and in vivo using human MEC xenograft models. We found that CRTC1-MAML2 fusion oncogene was required for the growth and survival of fusion-positive human MEC cancer cells in vitro and in vivo. The CRTC1-MAML2 oncoprotein induced the upregulation of the epidermal growth factor receptor (EGFR) ligand Amphiregulin (AREG) by co-activating the transcription factor CREB, and AREG subsequently activated EGFR signaling in an autocrine manner that promoted MEC cell growth and survival. Importantly, CRTC1-MAML2-positive MEC cells were highly sensitive to EGFR signaling inhibition. Therefore, our study revealed that aberrantly activated AREG-EGFR signaling is required for CRTC1-MAML2-positive MEC cell growth and survival, suggesting that EGFR-targeted therapies will benefit patients with advanced, unresectable CRTC1-MAML2-positive MEC.