Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China.
Int J Oncol. 2013 May;42(5):1578-88. doi: 10.3892/ijo.2013.1878. Epub 2013 Mar 29.
This study investigated the role of LOX in promoting invasion and metastasis of epithelial ovarian cancer in a hypoxic environment and its specific signal transduction pathway. Immunohistochemical detection of HIF-1α and LOX protein expression was performed on formalin-fixed paraffin sections of normal ovary, benign ovarian tumors, borderline and malignant epithelial ovarian tumor paraffin sample, using Mann-Whitney U test for independent comparisons and Wilcoxon signed-ranks test for paired comparisons. HIF-1α and LOX were knocked down in epithelial ovarian cancer cells (EOC), and HIF-1α/LOX regulation mechanism and LOX catalytic activity under hypoxia/reoxygenation microenvironment were explored. Cell migration and invasion ability in LOX inhibited HO8910 cells were investigated under hypoxia/reoxygenation conditions, using matrigel cell invasion and migration assays. We found that HIF-1α and LOX are highly expressed in epithelial ovarian cancer tissues, and the expression of both proteins is significantly correlated with the tumor grade, tumor diameter and lymph node metastasis. HIF-1α expression is positively correlated with the expression of LOX. Specifically, the expression of LOX and HIF-1α markedly increases under hypoxic conditions and decreases after reoxygenation. siRNA knockdown of LOX or β-aminoproprionitrile (βAPN), an inhibitor of LOX activity, that attenuates LOX activity, downregulates HIF-1α protein expression and inhibits HO8910 migratory and invasive abilities. LOX catalytic activity is significantly reduced under hypoxic conditions. Moreover, EOC cells display a marked increase in LOX-dependent FAK/AKT activation and cell migration following hypoxia/reoxygenation. Collectively, our study demonstrates that the hypoxia-HIF-1α, LOX-FAK/AKT pathway regulates the migration and invasion of epithelial ovarian cancer cells under hypoxia/reoxygenation conditions, thus, promoting metastasis of ovarian cancer.
本研究探讨了 LOX 在缺氧环境下促进上皮性卵巢癌侵袭转移中的作用及其特定的信号转导途径。采用 Mann-Whitney U 检验进行独立比较，Wilcoxon 符号秩检验进行配对比较，对正常卵巢、良性卵巢肿瘤、交界性和恶性上皮性卵巢肿瘤石蜡样本中 HIF-1α 和 LOX 蛋白表达进行了免疫组化检测。在缺氧/复氧微环境下，敲低上皮性卵巢癌细胞（EOC）中的 HIF-1α 和 LOX，探讨 HIF-1α/LOX 调控机制和 LOX 催化活性。在缺氧/复氧条件下，采用基质胶细胞侵袭和迁移实验研究 LOX 抑制 HO8910 细胞的迁移和侵袭能力。我们发现 HIF-1α 和 LOX 在卵巢上皮性癌组织中高表达，两种蛋白的表达均与肿瘤分级、肿瘤直径和淋巴结转移显著相关。HIF-1α 表达与 LOX 表达呈正相关。具体来说，LOX 和 HIF-1α 的表达在缺氧条件下明显增加，复氧后减少。LOX 或其活性抑制剂β-氨基丙腈（βAPN）的 siRNA 敲低可降低 LOX 活性，下调 HIF-1α 蛋白表达，并抑制 HO8910 的迁移和侵袭能力。LOX 催化活性在缺氧条件下显著降低。此外，EOC 细胞在缺氧/复氧后显示出明显增加的 LOX 依赖性 FAK/AKT 激活和细胞迁移。总之，我们的研究表明，缺氧-HIF-1α、LOX-FAK/AKT 通路调节上皮性卵巢癌细胞在缺氧/复氧条件下的迁移和侵袭，从而促进卵巢癌的转移。
