Sales Kurt J, Sutherland Jason R, Jabbour Henry N, Katz Arieh A
MRC/UCT Research Group for Receptor Biology, Institute of Infectious Disease and Molecular Medicine and Division of Medical Biochemistry, University of Cape Town, South Africa.
Biochim Biophys Acta. 2012 Oct;1823(10):1789-95. doi: 10.1016/j.bbamcr.2012.06.021. Epub 2012 Jun 23.
Cervical cancer is one of the leading gynecological malignancies in women. We have recently shown that seminal plasma (SP) can regulate the inflammatory cyclooxygenase-prostaglandin pathway and enhance the growth of cervical epithelial tumours in vivo by promoting cellular proliferation and alteration of vascular function. This study investigated the molecular mechanism whereby SP regulates vascular function using an in vitro model system of HeLa cervical adenocarcinoma cells and human umbilical vein endothelial cells (HUVECs). We found that SP rapidly enhanced the expression of the angiogenic chemokines, interleukin (IL)-8 and growth regulated oncogene alpha (GRO) in HeLa cells in a time-dependent manner. We investigated the molecular mechanism of SP-mediated regulation of IL-8 and GRO using a panel of chemical inhibitors of cell signalling. We found that treatment of HeLa cells with SP elevated expression of IL-8 and GRO by transactivation of the epidermal growth factor receptor, activation of extracellular signal-regulated kinase and induction of cyclooxygenase enzymes and nuclear factor kappa B. We investigated the impact of IL-8 and GRO, released from HeLa cells after treatment with SP, on vascular function using a co-culture model system of conditioned medium (CM) from HeLa cells, treated with or without SP, and HUVECs. We found that CM from HeLa cells induced the arrangement of endothelial cells into a network of tube-like structures via the CXCR2 receptor on HUVECs. Taken together our data outline a molecular mechanism whereby SP can alter vascular function in cervical cancers via the pro-angiogenic chemokines, IL-8 and GRO.
宫颈癌是女性主要的妇科恶性肿瘤之一。我们最近发现，精浆（SP）可调节炎症性环氧化酶 - 前列腺素途径，并通过促进细胞增殖和改变血管功能在体内增强宫颈上皮肿瘤的生长。本研究使用HeLa宫颈腺癌细胞和人脐静脉内皮细胞（HUVECs）的体外模型系统，研究了SP调节血管功能的分子机制。我们发现，SP能以时间依赖性方式迅速增强HeLa细胞中血管生成趋化因子、白细胞介素（IL）-8和生长调节致癌基因α（GRO）的表达。我们使用一组细胞信号化学抑制剂，研究了SP介导的IL-8和GRO调节的分子机制。我们发现，用SP处理HeLa细胞可通过表皮生长因子受体的反式激活、细胞外信号调节激酶的激活以及环氧化酶和核因子κB的诱导，提高IL-8和GRO的表达。我们使用来自经或未经SP处理的HeLa细胞的条件培养基（CM）与HUVECs的共培养模型系统，研究了SP处理后HeLa细胞释放的IL-8和GRO对血管功能的影响。我们发现，HeLa细胞的CM通过HUVECs上的CXCR2受体诱导内皮细胞排列成管状结构网络。综上所述，我们的数据概述了一种分子机制，即SP可通过促血管生成趋化因子IL-8和GRO改变宫颈癌中的血管功能。
