Department of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada.
Biochem Biophys Res Commun. 2010 Mar 12;393(3):371-6. doi: 10.1016/j.bbrc.2010.01.125. Epub 2010 Feb 12.
Pancreatic cancer is an aggressive malignancy with proclivity to early metastasis. High expression and activation of the collagenase matrix metalloproteinase-2 (MMP-2) have been found in human pancreatic cancer tissues, being these increased levels of active MMP-2 correlated to tumor invasion and metastasis. Hypoxia and reoxygenation (H-R) are critical pathophysiological conditions during ischemia-reperfusion injury, which has been shown to enhance both invasion and metastasis. In the present study, we investigated the effects of H-R on MMP-2 levels and the invasiveness properties of human pancreatic cancer cells PANC-1. Using specific inhibitors, we found that H-R treatment of these tumor cells induced secretion and activation of MMP-2, which was required for H-R-stimulated basement membrane degradation and cell invasion. Our results also indicate that signaling events involved in H-R-enhanced PANC-1 invasiveness comprehend PI3K-dependent activation of Rac1, which mediated the formation of NADPH-generated reactive oxygen species responsible for MMP-2 secretion and activation.
胰腺癌是一种侵袭性恶性肿瘤，具有早期转移的倾向。在人类胰腺癌组织中发现了胶原酶基质金属蛋白酶-2（MMP-2）的高表达和激活，这些活性 MMP-2 的增加水平与肿瘤侵袭和转移相关。缺氧和再氧合（H-R）是缺血再灌注损伤过程中的关键病理生理条件，已证明它可增强侵袭和转移。在本研究中，我们研究了 H-R 对人胰腺癌细胞 PANC-1 中 MMP-2 水平和侵袭特性的影响。使用特异性抑制剂，我们发现 H-R 处理这些肿瘤细胞诱导 MMP-2 的分泌和激活，这对于 H-R 刺激的基底膜降解和细胞侵袭是必需的。我们的结果还表明，参与 H-R 增强 PANC-1 侵袭性的信号事件包括 PI3K 依赖性 Rac1 的激活，其介导了 NADPH 产生的活性氧的形成，该活性氧负责 MMP-2 的分泌和激活。
