Oncogenic mutations of the PIK3CA gene in head and neck squamous cell carcinomas.
Oncogenic mutations of the PIK3CA gene in head and neck squamous cell carcinomas.
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DOI：
10.3892/ijo.32.1.101
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发表时间：
2008
影响因子：
5.2
通讯作者：
A. K. Murugan;N. T. Hong;Y. Fukui;A. K. Munirajan;N. Tsuchida
中科院分区：
文献类型：
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作者：
A. K. Murugan;N. T. Hong;Y. Fukui;A. K. Munirajan;N. Tsuchida
磷脂酰肌醇3-激酶（pi3k）是一种异二聚体脂质激酶，可调节细胞活性，如增殖、存活、运动和形态。最近的研究报道了p110 α (PIK3CA)， pi3激酶的催化亚基在人类癌症中发生体细胞突变。热点突变（E542K， E545K和H1047R）据报道具有较高的致癌潜力。尽管PIK3CA突变在有限种族的头颈部鳞状细胞癌（HNSCC）中有报道，但与HNSCC相关的PIK3CA突变的功能后果尚未得到研究。PIK3CA突变存在时，PI3K信号相关基因（PTEN-RAS-EGFR）的状态尚未报道。在这项研究中，我们分析了54个样本中的PIK3CA外显子9和20，包括17个HNSCC细胞系，19个印度和18个越南原发肿瘤。我们在29.4%（5/17）的HNSCC细胞系中发现突变，在印度肿瘤中发现10.5%（2/19）的突变，在越南肿瘤中发现无突变（0/18）。在细胞系中发现了两个纯合子PIK3CA突变，在印度肿瘤中发现了一个具有致癌性的新插入突变。PI3K信号相关基因分析显示，PIK3CA和PTEN突变是互斥的，但PTEN突变在HNSCC中并不常见。而PIK3CA突变与H-RAS突变共存。此外，PIK3CA突变与EGFR扩增是互斥的。我们在HNSCC中发现的5个突变体均表现出PI3激酶活性升高，与PIK3CA野生型相比，具有生长因子独立的更高集落形成效率、形态变化、更高的迁移和侵袭率。我们的研究首次检测了与HNSCC相关的PIK3CA突变的致癌潜力，并报道了印度和越南种族的PIK3CA突变。这些结果表明，PIK3CA突变在HNSCC中可能具有致癌作用，并可能显著促进HNSCC的癌变，为治疗预防提供了有吸引力的靶点。
Phosphatidylinositol 3-kinases (PI3Ks) are heterodimeric lipid kinases that regulate cellular activities such as proliferation, survival, motility and morphology. Recent studies reported that the p110alpha (PIK3CA), catalytic subunit of PI3-kinase is somatically mutated in human cancers. Hot- spot mutations (E542K, E545K and H1047R) are reported to have higher oncogenic potential. Although PIK3CA mutations were reported in head and neck squamous cell carcinomas (HNSCC) of limited ethnicity, the functional consequences of HNSCC-associated PIK3CA mutations have not been examined. Status of PI3K signaling related genes (PTEN-RAS-EGFR) in the presence of PIK3CA mutation have not been reported. In this study, we analyzed exons 9 and 20 of PIK3CA in 54 samples, including 17 HNSCC cell lines, 19 Indian and 18 Vietnamese primary tumors. We found mutations in 29.4% (5/17) of HNSCC cell lines, 10.5% (2/19) of Indian tumors and no mutation (0/18) in Vietnamese tumors. Two homozygous PIK3CA mutations were found in cell lines and a novel insertion mutation with oncogenicity in Indian tumor. Analysis of PI3K signaling related genes showed that PIK3CA and PTEN mutations were mutually exclusive, though PTEN mutation is uncommon in HNSCC. However, PIK3CA mutation coexisted with H-RAS mutation. Furthermore, PIK3CA mutations were mutually exclusive to EGFR amplification. All the 5 mutants that we found in HNSCC, showed increased PI3 kinase activities, followed by growth factor independent higher colony forming efficiency, changes in morphology, higher rates of migration and invasion compared with PIK3CA wild-type. Our study is the first to examine the oncogenic potential of PIK3CA mutants associated with HNSCC and report on PIK3CA mutations in Indian and Vietnamese ethnicity. These results suggest that PIK3CA mutations in HNSCC are likely to be oncogenic and may significantly contribute to HNSCC carcinogenesis and pave attractive target for therapeutic prevention.