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.