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Hypoxia promotes metastatic potential of tumor cells by largely unknown mechanisms. Hypoxia inducible factor (HIF) is a heterodimeric transcription factor consisting of alpha and beta (ARNT) subunits and plays an important role in tumor microenvironment. CXCR4 is a cell surface receptor that has been shown to mediate the metastasis of various tumors. CXCR4 induction by hypoxia is dependent on both activation of HIF and transcript stabilization. To investigate the mechanisms involved in hypoxia-induced metastasis and hypoxia-mediated chemokine receptor CXCR4 expression, we used lentiviral vector mediated RNA interfering (RNAi) to knock down expression of HIF-1alpha or HIF-2alpha in two NSCLC cell lines to investigate HIF-dependent invasion, migration and adhesion. Here we show that: (1) hypoxia is an important factor in regulating CXCR4 mediated metastasis and the cells exhibited reducing invasion, adhesion and migration in response to CXCL12 after knocking down HIF. (2) HIF-1alpha and HIF-2alpha are essential for hypoxic cellular response to cancer invasion and adhesion through upregulation of CXCR4. HIF-1alpha and HIF-2alpha are playing important roles in tumor metastasis, which may offer for future intervention strategies. We also show that the lentivirus mediated RNAi technology is very effective on knocking down gene expression.