Abstract
HIF1α is well known for its role in induction of metastasis leading to cancer progression.LOXL2 and LOX can induce epithelial‐to‐mesenchymal transition (EMT) of tumor cells and turn them into more aggressive phenotype. Recent findings show that LOX expression can be activated by both hypoxia and reactive oxygen species (ROS) via HIF1 pathway, suggesting complex regulation of LOX in EMT in vivo. To address this, we studied the mechanism of regulation of LOXL2 gene expression in human colon cancer HCT116 cells with impaired mitochrondrial respiration (SCO2‐/‐ mutant).q‐PCR showed that under normoxic conditions (21% O2) expression of LOXL2 gene in SCO2‐/‐ cells, which have increased ROS production, is 8 times higher than in wild type. Culturing of SCO2‐/‐ cells for 1 week with ROS scavenger N‐acetylcysteine (NAC) or inhibitor of HIF‐α signaling FM19G11 under normoxia led to twofold decrease in LOXL2 expression, suggesting direct involvement of ROS/HIF1 axis in LOXL2 gene expression in this cell line. However, we saw no statistical difference in LOXL2 expression in SCO2‐/‐ cells treated with NAC under the hypoxic conditions (3% O2), confirming that ROS levels are decreased in hypoxia and are less involved in regulation of LOXL2. At the same time treatment of SCO2‐/‐ cells with FM19G11 led to twofold decrease in expression of LOXL2, thus demonstrating the active role of HIF pathway. Altogether these data demonstrate that different pathways can be involved in HIF1 dependent expression of LOXL2 under hypoxia and oxidative stress. This mechanism can play important role in vivo in cancer progression mediated by LOXs.Supported by SFI.
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