Overexpression of PIK3CA in head and neck squamous cell carcinoma is associated with poor outcome and activation of the YAP pathway
Overexpression of PIK3CA in head and neck squamous cell carcinoma is associated with poor outcome and activation of the YAP pathway
复制标题
DOI：
10.1016/j.oraloncology.2018.02.014
复制
发表时间：
2018-04-01
期刊：
影响因子：
4.8
通讯作者：
Lorz, Corina
中科院分区：
文献类型：
--
作者：
Garcia-Escudero, Ramon;Segrelles, Carmen;Lorz, Corina
目的：磷脂酰肌醇3-激酶催化亚基α（PIK 3CA）通常在许多人类肿瘤中发生改变，导致p110 α酶活性激活，刺激生长因子非依赖性细胞生长。PIK 3CA改变如突变、基因扩增和过表达在头颈部鳞状细胞癌（HNSCC）中是常见的。我们的目的是探讨这些改变和临床结果是如何关联的，以及所涉及的分子机制。材料和方法：突变和拷贝数变化PIK 3CA，全基因组表达谱，分析了原发性HNSCC肿瘤的癌症基因组图谱（TCGA）队列（n=243）。结果在来自拉科鲁尼亚大学医院（UHAC，n=62）的独立队列中进行了验证。PIK 3CA基因蛋白产物（PI 3 K p110 α）和核雅普的表达在来自大学医院12 de Octubre（UH 12 O，n=91）的队列中的组织微阵列中进行评估。对基因表达、转录因子和蛋白质特征的研究表明，参与器官大小、干细胞维持和肿瘤发生的Hippo-YAP通路的激活可能是PI 3 KCA过表达肿瘤中肿瘤进展的基础。组织阵列显示PI 3 K p110 α水平与HNSCC肿瘤中的雅普核定位相关。结论：HNSCC原发性肿瘤中PIK 3 CA的高表达鉴定了高复发风险的患者。在这些肿瘤中，进展可能依赖于Hippo-YAP通路而不是经典的Akt/mTOR通路。这一观察结果可能对患者的治疗选择具有重要意义。
Objectives: Phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) is commonly altered in many human tumors, leading to the activation of p110 alpha enzymatic activity that stimulates growth factor-independent cell growth. PIK3CA alterations such as mutation, gene amplification and overexpression are common in head and neck squamous cell carcinoma (HNSCC) and. We aim to explore how these alterations and clinical outcome are associated, as well as the molecular mechanisms involved.Material and methods: Mutation and copy-number variation in PIK3CA, and whole-genome expression profiles, were analyzed in primary HNSCC tumors from The Cancer Genome Atlas (TCGA) cohort (n=243). The results were validated in an independent cohort form the University Hospital of A Coruna (UHAC, n=62). Expression of the PIK3CA gene protein product (PI3K p110 alpha) and nuclear YAP were assessed in tissue microarrays in a cohort from the University Hospital 12 de Octubre (UH12O, n=91).Results: Only high expression of the PIK3CA gene was associated with poor clinical outcome. The study of gene expression, transcription factor and protein signatures suggested that the activation of the Hippo-YAP pathway, involved in organ size, stem cell maintenance and tumorigenesis, could underlie tumor progression in PI3KCA overexpressing tumors. Tissue arrays showed that PI3K p110 alpha levels correlated with YAP nuclear localization in HNSCC tumors.Conclusions: High expression of PIK3CA in HNSCC primary tumors identifies patients at high risk for recurrence. In these tumors, progression could rely on the Hippo-YAP pathway instead of the canonical Akt/mTOR pathway. This observation could have important implications in the therapeutic options for patients.