【作者】 陈成；

【导师】 胡俊波；

【作者基本信息】 华中科技大学 ， 外科学， 2013， 博士

【摘要】 血管生成在肿瘤的发生和发展中发挥关键性作用；VEGF是调控血管生成的一个重要生长因子。PI3K通路在血管生成的调控上发挥重要作用,但是PI3K的调节亚基在肿瘤血管生成方面的功能和对VEGF表达的影响还很不明确。在本研究中,我们探寻p55PIK,一个由PIK3R3基因编码的PI3K的调节亚基,在肿瘤血管生成方面的作用。我们发现在结肠癌细胞中高表达p55PIK可以明显促进HIF-1α的表达,继而促进VEGF蛋白的分泌,反之亦然。在体内和体外试验中,高表达p55PIK均可以促进肿瘤的血管生成。而且我们实验结果提示p55PIK促进HIF-1α的表达,而对其稳定性无明显影响,这一作用是通过调控NF-κB通路实现的,而与PI3K/Akt通路和ERK通路无关。我们的研究结果提示p55PIK在癌细胞介导的肿瘤血管生成中发挥重要作用,并且能够明显促进肿瘤的生长。这些提示我们p55PIK可能是一个潜在的临床上针对肿瘤血管生成治疗的重要靶点。更多还原

【Abstract】 Angiogenesis plays a key process in the tumor growth; vascular growth factor (VEGF) is an important mediator of angiogenesis. PI3K plays essential roles in angiogenesis, however, however, the mechanisms and specific functions of individual isoforms of PI3K members in tumor angiogenesis regulation are still not folly understood. In this study, we try to evaluate the role of p55PIK, a PI3K regulatory subunit encoded by PIK3R3gene, in tumor angiogenesis. We found that overexpressing p55PIK in cancer cells could up-regulate HIF-1α expression and promoted VEGF expression. Furthermore, over-expressing p55PIK promoted tumor angiogenesis in vivo and in vitro. Moreover, data indicated enhanced HIF-la expression by p55PIK-PI3K depended on its ability to activate NF-κB signaling pathway, especially to increase the phosphorylation of p65subunits of NF-κB, but not AKT or ERK signaling. Our study showed p55PIK-PI3K was essential in regulating cancer cells-mediated angiogenesis and contributed to tumor growth and that the p55PIK provides a potential and specific target for new anti-angiogenesis drug development.更多还原