PTEN Deficiency Contributes to the Development and Progression of Head and Neck Cancer
PTEN Deficiency Contributes to the Development and Progression of Head and Neck Cancer
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DOI：
10.1593/neo.121024
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发表时间：
2013-05-01
期刊：
影响因子：
4.8
通讯作者：
Gutkind, J. Silvio
中科院分区：
文献类型：
--
作者：
Squarize, Cristiane H.;Castilho, Rogerio M.;Gutkind, J. Silvio
头颈癌的测序为这种癌症类型中最常见的基因改变提供了蓝图。它们包括 Notch、p53 和 p16(ink4a) 肿瘤抑制基因的失活突变，以及 PIK3CA 和 RAS 癌基因的非重叠激活突变或肿瘤抑制基因 PTEN 的失活。值得注意的是，这些遗传改变以及表观遗传变化导致磷酸肌醇 3 激酶 (PI3K)/AKT/哺乳动物雷帕霉素靶点 (mTOR) 通路活性增加，该通路存在于大多数头颈鳞状细胞癌 (HNSCC) 中。此外，我们在此表明，大约 30% 的 HNSCC 表现出 PTEN 表达降低。我们通过将口腔内施用烟草替代物 4-硝基喹啉 1-氧化物与显示 PTEN 表达减少的遗传定义的动物模型相结合，对这一发现的生物学相关性提出了挑战，这是通过使用角蛋白启动子 14 CRE-lox 系统有条件删除 Pten 来实现的。这为 HNSCC 提供了一个特定的遗传和环境定义的动物模型，导致口腔特异性癌症的快速发展。在这些实验条件下，对照小鼠没有出现 HNSCC 病变。相比之下，大多数携带 Pten 缺陷的小鼠在舌头和口底的外侧缘和腹侧部分出现多个 SCC 病变，这些是人类 HNSCC 的首选解剖部位。总体而言，我们的研究强调了 PTEN 表达减少和/或失活在 HNSCC 进展中可能的临床相关性，而 Pten 缺失与暴露于烟草致癌物或其替代物的组合可能提供独特的实验模型系统来研究 HNSCC 患者的新型分子靶向治疗。
The sequencing of the head and neck cancer has provided a blueprint of the most frequent genetic alterations in this cancer type. They include inactivating mutations in Notch, p53, and p16(ink4a) tumor suppressor genes, in addition to nonoverlapping activating mutations of the PIK3CA and RAS oncogenes or inactivation of the tumor suppressor gene PTEN. Notably, these genetic alterations, along with epigenetic changes, result in increased activity of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, which is present in most head and neck squamous cell carcinomas (HNSCCs). Moreover, we show here that approximately 30% of HNSCCs exhibit reduced PTEN expression. We challenged the biologic relevance of this finding by combining the intraoral administration of a tobacco surrogate, 4-nitroquinoline 1-oxide, with a genetically defined animal model displaying reduced PTEN expression, achieved by the conditional deletion of Pten using the keratin promoter 14 CRE-lox system. This provided a specific genetic and environmentally defined animal model for HNSCC that resulted in the rapid development of oral-specific carcinomas. Under these experimental conditions, control mice did not develop HNSCC lesions. In contrast, most mice harboring Pten deficiency developed multiple SCC lesions in the lateral border and ventral part of the tongue and floor of the mouth, which are the preferred anatomic sites for human HNSCC. Overall, our study highlights the likely clinical relevance of reduced PTEN expression and/or inactivation in HNSCC progression, while the combined Pten deletion with exposure to tobacco carcinogens or their surrogates may provide a unique experimental model system to study novel molecular targeted treatments for HNSCC patients.