Hypoxia induced CCR7 expression via HIF-1alpha and HIF-2alpha correlates with migration and invasion in lung cancer cells.

Hypoxia, a common phenomenon in human solid tumors, is associated with invasion and metastasis in various tumors. Hypoxia inducible factors (HIFs) are key molecules in the hypoxic response, and regulate the activation of specific genes, which mediate many of the adaptations to hypoxia. CC chemokine receptor 7 (CCR7) has been shown to play a critical role in cell chemotaxis and homing, which are key steps in cancer metastasis. A study has demonstrated that hypoxia could upregulate CCR7 in breast cancer cells. The CCR7 gene presents hypoxia response element (HRE; (A)/(G)CGTG). We presumed that hypoxia induced upregulation of HIFs promoted the expression of CCR7 facilitating tumor cells invasion and metastasis. In this study, we firstly examined the relationship of CCR7 and HIF-1alpha, HIF-2alpha in 94 cases non-small cell lung cancer (NSCLC) tissues by immunohistochemistry. The results showed that CCR7 expression correlated positively with HIF-1alpha and HIF-2alpha, all of them correlated with clinical stage and lymph node metastasis. Then, we investigated whether hypoxia induce the expression of CCR7 through HIF-1alpha and/or HIF-2alpha and observed the effects of upregulated CCR7 on the migration and invasion of lung cancer cells. We found that hypoxia induced HIF-1alpha and HIF-2alpha expression, which upregulated CCR7 expression; inhibiting HIF-1alpha or HIF-2alpha expression in BE1 and A549 cells by RNAi led to the decrease of CCR7 expression, inhibition of migratory and invasive abilities, and the effects of HIF-1alpha were more significant. Moreover, the migration and invasion of BE1 cells were increased as well as the expression of p-ERK1/2 after CCR7 transfection, but the cells invasive ability was inhibited after blocking p-ERK1/2 with PD98059 and CCR7 with specific antibody. In summary, our study demonstrated that hypoxia-HIF-1alpha, 2alpha-CCR7-ERK1/2 pathway could regulate the migration and invasion of lung cancer cells under hypoxic conditions and promote metastasis of lung cancer.