Zhang Lin, Yang Nuo, Katsaros Dionyssios, Huang Wei, Park Jin-Wan, Fracchioli Stefano, Vezzani Cristina, Rigault de la Longrais Irene A, Yao Weijia, Rubin Stephen C, Coukos George
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Cancer Res. 2003 Jul 15;63(14):4225-31.
The gene of phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) has been implicated as an oncogene in ovarian cancer [L. Shayesteh et al., Nat. Genet., 21: 99-102, 1999]. In this study, we examined the expression of PIK3CA mRNA and its p110alpha protein product in human ovarian carcinoma and investigated its role in regulating angiogenesis via vascular endothelial growth factor (VEGF). PIK3CA mRNA was detected in 66.6% of stage I and 93.9% of advanced stage ovarian cancer specimens and in all 17 ovarian cancer cell lines. PIK3CA mRNA levels were significantly higher in invasive carcinomas compared with benign and low malignant potential neoplasms (P = 0.007), but no significant difference was seen between early and advanced stage carcinomas (P = 0.812). Strong expression of immunoreactive p110alpha was detected in tumor cells and/or stroma endothelium. PIK3CA expression in vivo positively correlated, both at the mRNA and the protein level, with the expression of VEGF as well as with the extent of microvascular development. Furthermore, PIK3CA mRNA overexpression positively correlated with increased proliferation and decreased apoptosis of tumor cells in vivo. In vitro, PIK3CA expression positively correlated with the expression of VEGF in ovarian cancer cells, whereas the phosphatidylinositol 3'-kinase inhibitor Ly294002 reduced both the constitutive and inducible expression of hypoxia-inducible factor-1alpha at the mRNA and protein levels and abrogated VEGF up-regulation by glucose starvation. Furthermore, Ly294002 suppressed cell proliferation and, at higher doses, induced marked apoptosis in ovarian cancer cells. Collectively, these data strongly indicate that PIK3CA supports ovarian cancer growth through multiple and independent pathways affecting cell proliferation, apoptosis and angiogenesis, and plays an important role in ovarian cancer progression.
磷脂酰肌醇3激酶催化亚基α（PIK3CA）基因已被认为是卵巢癌中的一种癌基因[L. Shayesteh等人，《自然遗传学》，21: 99 - 102，1999]。在本研究中，我们检测了PIK3CA mRNA及其p110α蛋白产物在人卵巢癌中的表达，并研究了其通过血管内皮生长因子（VEGF）调节血管生成的作用。在66.6%的I期和93.9%的晚期卵巢癌标本以及所有17种卵巢癌细胞系中检测到PIK3CA mRNA。与良性和低恶性潜能肿瘤相比，浸润性癌中的PIK3CA mRNA水平显著更高（P = 0.007），但早期和晚期癌之间未观察到显著差异（P = 0.812）。在肿瘤细胞和/或基质内皮中检测到免疫反应性p110α的强表达。体内PIK3CA表达在mRNA和蛋白水平上均与VEGF表达以及微血管发育程度呈正相关。此外，PIK3CA mRNA过表达与体内肿瘤细胞增殖增加和凋亡减少呈正相关。在体外，PIK3CA表达与卵巢癌细胞中VEGF的表达呈正相关，而磷脂酰肌醇3'-激酶抑制剂Ly294002在mRNA和蛋白水平上均降低了缺氧诱导因子-1α的组成性和诱导性表达，并消除了葡萄糖饥饿引起的VEGF上调。此外，Ly294002抑制细胞增殖，并且在较高剂量时诱导卵巢癌细胞显著凋亡。总体而言，这些数据强烈表明PIK3CA通过影响细胞增殖、凋亡和血管生成的多个独立途径支持卵巢癌生长，并在卵巢癌进展中起重要作用。
