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

Abstract

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-1α, HIF-2α in 94 cases non-small cell lung cancer (NSCLC) tissues by Immunohistochemistry. The results showed that CCR7 expression correlated positively with HIF-1α and HIF-2α, all of them correlated with clinical stage and lymph node metastasis. Then, we investigated whether hypoxia induce the expression of CCR7 through HIF-1α and/or HIF-2α and observed the effects of upregulated CCR7 on the migration and invasion of lung cancer cells. We found that hypoxia induced HIF-1α and HIF-2α expression, which upregulated CCR7 expression; inhibiting HIF-1α or HIF-2α 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-1α 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-1α, 2α-CCR7-ERK1/2 pathway could regulate the migration and invasion of lung cancer cells under hypoxic conditions and promote metastasis of lung cancer.

HIF-1α and HIF-2α correlate with migration and invasion in gastric cancer

“…This result was consistent with previous reports on HIF-1α and HIF-2α expression in lung cancer. 13 We hypothesized that HIF-1α and HIF-2α together were involved in the migration and invasion of gastric cancer. To test this hypothesis, we examined HIF-1α and HIF-2α in the gastric cancer cell line SGC7901 under hypoxia.…”

Impact of the Prolymphangiogenic Crosstalk in the Tumor Microenvironment on Lymphatic Cancer Metastasis

“…In one study the authors suggest that CCR7 enhances metastasis by upregulating MMP-9 expression [59]. Li et al showed that hypoxia may induce CCR7 expression on tumor cells to stimulate migration and invasion of lung cancer cells, using the HIF1α and HIF2α pathway [60]. …”

Fine Mapping Reveals That Promotion Susceptibility Locus 1 (Psl1) Is a Compound Locus With Multiple Genes That Modify Susceptibility to Skin Tumor Development

“…Binding to CCRL1 results in internalization and degradation of these ligands (Comerford et al 2006), which attenuates the immune response (Heinzel et al 2007). Recent reports have shown that the CCRL1 ligands promote proliferation and prevent apoptosis (Wang et al 2005; Li et al 2009; Shen et al 2009; Johnson et al 2010; Xu et al 2011, 2012), suggesting that increased expression of Ccrl1 may reduce tumor response through chemokine depletion. This idea is further supported by the observation of a significantly higher rate of tumor growth in wild-type BALB/c mice compared to plt mice, which lack CCL19 and CCL21, implanted with a syngeneic squamous cell carcinoma cell line (Mburu et al 2006).…”