PIK3CA is implicated as an oncogene in ovarian cancer
PIK3CA is implicated as an oncogene in ovarian cancer
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DOI：
10.1038/5042
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发表时间：
1999-01-01
期刊：
影响因子：
30.8
通讯作者：
Gray, JW
中科院分区：
文献类型：
--
作者：
Shayesteh, L;Lu, YL;Gray, JW
卵巢癌是导致妇科恶性肿瘤死亡的主要原因，也是美国女性癌症死亡的第四大原因(1)，但对其分子病因知之甚少。使用比较基因组杂交（CGH）的研究揭示了几个复发的、异常的、DNA序列拷贝数（2-4）的区域，这些区域可能编码参与疾病发生或进展的基因。在大约40%的卵巢癌(2)和其他癌症(5)中，发现3q26的一个拷贝数增加的区域含有PIK3CA，它编码磷脂酰肌醇3-激酶（pi3 -激酶）的p110 α催化亚基。PIK3CA拷贝数与pi3激酶活性之间的关联使PIK3CA成为候选癌基因，因为广泛的癌症相关功能与pi3激酶介导的信号传导有关(6)。这些包括增殖(7)、葡萄糖转运和分解(8)、细胞粘附(9)、细胞凋亡（10）、RAS信号传导6和致癌转化（11-14）。此外，pl3激酶的下游效应物AKT1和AKR已被发现在包括卵巢癌在内的人类肿瘤中被扩增（15,16）或激活（17）。我们在这里表明，PIK3CA在卵巢癌中的拷贝数经常增加，拷贝数的增加与PIK3CA转录，p110 α蛋白表达和po激酶活性的增加有关，并且用pi3激酶抑制剂LY294002治疗可减少增殖并增加凋亡。我们的观察结果表明，PIK3CA是一种在卵巢癌中起重要作用的致癌基因。
Ovarian cancer is the leading cause of death from gynecological malignancy and the fourth leading cause of cancer death among American women(1), yet little is known about its molecular aetiology. Studies using comparative genomic: hybridization (CGH) have revealed several regions of recurrent, abnormal, DNA sequence copy number(2-4) that may encode genes involved in the genesis or progression of the disease. One region at 3q26 found to be increased in copy number in approximately 40% of ovarian(2) and other(5) cancers contains PIK3CA, which encodes the p110 alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3-kinase). The association between PIK3CA copy number and PI3-kinase activity makes PIK3CA a candidate oncogene because a broad range of cancer-related functions have been associated with PI3-kinase mediated signalling(6). These include proliferation(7), glucose transport and catabotism(8), cell adhesion(9), apoptosis(10), RAS signalling6 and oncogenic transformation(11-14). In addition, downstream effecters of Pl3-kinase, AKT1 and AKR, have been found to be amplified(15,16) or activated(17) in human tumours, including ovarian cancer. We show here that PIK3CA is frequently increased in copy number in ovarian cancers, that the increased copy number is associated with increased PIK3CA transcription, p110 alpha protein expression and PO-kinase activity and that treatment with the PI3-kinase inhibitor LY294002 decreases proliferation and increases apoptosis. Our observations suggest PIK3CA is an oncogene that has an important role in ovarian cancer.