Hypoxic Microenvironment Effects on Matrix Metalloproteinases' Expression and Enzymatic Activity, and HIFs'...

The hypoxic tumor microenvironment (TME) promotes metastasis, in which matrix metalloproteinases (MMPs) play a central role. The present work aimed to analyze the effects of hypoxia on MMP expression and enzymatic activity, as well as hypoxia-inducible factor (HIF) expression in different non-small cell lung cancer (NSCLC) cells. Cells were cultured in 1% O₂ for 6 and 12 h, and the effects of hypoxia on MMPs and HIFs were analyzed using Western blotting and zymography. The highest MMP-2 protein expression was detected in CALU-1 (p ≤ 0.003) and A549 cells (p ≤ 0.006) at 6 and 12 h, respectively. Higher levels of MMP-9 were detected in CALU-1 (p ≤ 0.003) at 6 h and in A549 cells (p ≤ 0.04) at 12 h. MMP-2 and MMP-9 had the highest enzymatic activity in SKMES-1 cells (p ≤ 0.003). Increased HIF-1α levels were detected in A427 (p ≤ 0.04) at 6 h and in SKLU-1 cells (p ≤ 0.01) at 12 h, while higher HIF-2α expression was found in SKMES-1 at 6 h and 12 h (p ≤ 0.04). In conclusion, although hypoxia induces changes in MMP-2 and MMP-9 expression in NSCLC cells through HIF-dependent or HIF-independent pathways, these effects are not necessarily similar to those observed in enzymatic activity and differ between cell lines.