Studies of type IV collagenase regulation by hypoxia

Recent data suggest that patients with more hypoxic solid tumors are more likely to develop metastases and die. We speculated that upregulation of the metastasis-associated type IV collagenase MMP-9 (gelatinase B) by hypoxia might be correlated with the increased risk of distant failure in patients with hypoxic tumors. The promoter for MMP-9 contains consensus binding sites for the transcription factors NFkappaB and AP-1 which are upregulated under hypoxic conditions in HeLa cells and these transcription factors are critical to transcriptional activation of the MMP-9 gene. A variety of tumor cell lines were examined for induction of MMP-9 and the related protease MMP-2 under hypoxic conditions. Although hypoxia did upregulate MMP-9 in one alveolar rhabdomyosarcoma cell line, we were unable to demonstrate a consistent hypoxia-mediated increase in MMP-9 protein, RNA, or transcriptional activity measured with reporter constructs. These results suggest that MMP-9 expression is not directly affected by exposure to hypoxia in vitro.