Hypoxia Potentiated Lung Cancer Cell Migration and Invasion by up-regulating HIF1/JAK2/STAT3 Axis and Activating MMP13 Transcription

Excessive aggressive migration and invasion are important factors that increase the mortality of cancer patients. Matrix metalloproteinase 13 (MMP13) expression is positively correlated with lung cancer malignancy. However, the mechanism underlying an elevated MMP13 expression is not clearly defined. In this study, we demonstrated that hypoxia induced by CoCl2 enhanced the expression of HIF1 alpha, JAK2, STAT3 and MMP13 in A549 cells. A positive correlation between HIF1 alpha and MMP13 expression was observed in lung adenocarcinoma patients. Mechanically, hypoxia upregulated HIF1 alpha/JAK2/STAT3 signal axis, promoted transcription factor STAT3 to bind to MMP13 promoter region, and activated MMP13 transcription, finally promoted cell invasion and migration. However, stattic (STAT3 inhibitor) could reverse this effect caused by STAT3 in A549 cells. Together our data indicated that hypoxia might promote lung cancer cell migration and invasion through the HIF1 alpha/JAK2/STAT3 axis by activating MMP13 transcription. MMP13 could be a promising therapeutic target for lung adenocarcinoma metastasis. Hypoxia promoted cell invasion and migration in A549 cells.STAT3, but not traditionally believed HIF1 alpha, primarily acted as a transcription factor of MMP13.