PIK3CA mutation is an oncogenic aberration at advanced stages of oral squamous cell carcinoma
PIK3CA mutation is an oncogenic aberration at advanced stages of oral squamous cell carcinoma
复制标题
DOI：
10.1111/j.1349-7006.2006.00343.x
复制
发表时间：
2006-12-01
期刊：
影响因子：
5.7
通讯作者：
Inazawa, Johji
中科院分区：
文献类型：
--
作者：
Kozaki, Ken-ichi;Imoto, Issei;Inazawa, Johji
磷脂酰肌醇3-激酶（PI 3 K）是一类调节多种细胞过程的异二聚体脂质激酶。已在各种人类癌症中报道了主要在PIK 3CA的螺旋（外显子9）和激酶（外显子20）结构域内的基因扩增和体细胞突变，其编码PI 3 K的110-kDa催化亚基并定位于3q 26。在此，研究了14个人口腔鳞状细胞癌（OSCC）细胞系和108个原发性OSCC肿瘤的第9和20外显子的激活突变以及PIK 3CA的扩增。通过基因组DNA测序，在21.4%（3/14）的OSCC细胞系和7.4%（8/108）的OSCC肿瘤中鉴定出PIK 3CA第9和第20外显子的错义突变。PIK 3CA的拷贝数增加，虽然很小，但使用定量实时PCR在57.1%（8/14）的OSCC细胞系和16.7%（18/108）的OSCC肿瘤中检测到。观察到PIK 3CA的体细胞突变与疾病分期之间的显著相关性：IV期（16.1%，5/31）的突变频率高于早期（I-III期）的亚组（3.9%，3/77; P = 0.042，Fisher提取物检验）。相反，在所有阶段中以相似的频率观察到PIK 3CA的扩增。尽管扩增，但与没有突变的OSCC细胞系相比，在具有PIK 3CA突变的OSCC细胞系中AKT高度磷酸化。结果表明，PIK 3CA基因的体细胞突变可能发生在OSCC发展的后期，并通过PI 3 K-AKT信号通路在癌症进展中发挥关键作用。
Phosphatidylinositol 3-kinases (PI3K) are a group of heterodimeric lipid kinases that regulate many cellular processes. Gene amplification and somatic mutations mainly within the helical (exon 9) and kinase (exon 20) domains of PIK3CA, which encode the 110-kDa catalytic subunit of PI3K and are mapped to 3q26, have been reported in various human cancers. Herein, 14 human oral squamous cell carcinoma (OSCC) cell lines and 108 primary OSCC tumors were investigated for activating mutations at exons 9 and 20 as well as amplifications in PIK3CA. PIK3CA missense mutations in exons 9 and 20 were identified in 21.4% (3/14) of OSCC cell lines and 7.4% (8/108) of OSCC tumors by genomic DNA sequencing. An increase in the copy number of PIK3CA, although small, was detected in 57.1% (8/14) of OSCC lines and 16.7% (18/108) of OSCC tumors using quantitative real-time PCR. A significant correlation between somatic mutations of PIK3CA and disease stage was observed: the frequency of mutations was higher in stage IV (16.1%, 5/31) than in a subset of early stages (stages I-III) (3.9%, 3/77; P = 0.042, Fisher's extract test). In contrast, the amplification of PIK3CA was observed at a similar frequency among all stages. AKT was highly phosphorylated in OSCC cell lines with PIK3CA mutations compared to those without mutations, despite the amplification. The results suggest that somatic mutations of the PIK3CA gene are likely to occur late in the development of OSCC, and play a crucial role through the PI3K-AKT signaling pathway in cancer progression.