Liang Shun, Yang Nuo, Pan Yue, Deng Shan, Lin Xiaojuan, Yang Xiaojun, Katsaros Dionyssios, Roby Katherine F, Hamilton Thomas C, Connolly Denise C, Coukos George, Zhang Lin
Center for Research on the Early Detection and Cure of Ovarian Cancer, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2009;4(1):e4295. doi: 10.1371/journal.pone.0004295. Epub 2009 Jan 27.
The Phosphatidylinositol 3'-kinase is a key regulator in various cancer-associated signal transduction pathways. Genetic alterations of its catalytic subunit alpha, PIK3CA, have been identified in ovarian cancer. Our in vivo data suggests that PIK3CA activation is one of the early genetic events in ovarian cancer. However, its role in malignant transformation of ovarian surface epithelium (OSE) is largely unclear.
METHODOLOGY/PRINCIPAL FINDINGS: Using the Müllerian inhibiting substance type II receptor (MISIIR) promoter, we generated transgenic mice that expressed activated PIK3CA in the Müllerian epithelium. Overexpression of PIK3CA in OSE induced remarkable hyperplasia, but was not able to malignantly transform OSE in vivo. The consistent result was also observed in primary cultured OSEs. Although enforced expression of PIK3CA could not induce OSE anchorage-independent growth, it significantly increased anchorage-independent growth of OSE transformed by mutant K-ras.
CONCLUSIONS/SIGNIFICANCE: While PIK3CA activation may not be able to initiate OSE transformation, we conclude that activation of PIK3CA may be an important molecular event contributing to the maintenance of OSE transformation initiated by oncogenes such as K-ras.
磷脂酰肌醇3'-激酶是各种癌症相关信号转导途径中的关键调节因子。在卵巢癌中已发现其催化亚基α（PIK3CA）的基因改变。我们的体内数据表明，PIK3CA激活是卵巢癌早期的基因事件之一。然而，其在卵巢表面上皮（OSE）恶性转化中的作用尚不清楚。
方法/主要发现：利用苗勒管抑制物质II型受体（MISIIR）启动子，我们构建了在苗勒管上皮中表达活化PIK3CA的转基因小鼠。OSE中PIK3CA的过表达诱导了显著的增生，但在体内未能使OSE发生恶性转化。在原代培养的OSE中也观察到了一致的结果。虽然PIK3CA的强制表达不能诱导OSE非锚定依赖生长，但它显著增加了由突变型K-ras转化的OSE的非锚定依赖生长。
结论/意义：虽然PIK3CA激活可能无法启动OSE转化，但我们得出结论，PIK3CA激活可能是一个重要的分子事件，有助于维持由K-ras等癌基因引发的OSE转化。
