A feed-forward loop between nuclear translocation of CXCR4 and HIF-1α promotes renal cell carcinoma metastasis

CXC chemokine receptor 4 (CXCR4) has been suggested to play a critical role in cancer metastasis. Some studies have described CXCR4 nuclear localization in metastatic lesions of renal cell carcinoma (RCC), which has been suggested to be correlated with cancer metastasis. However, the underlying mechanism and clinical significance of CXCR4 nuclear localization remains unknown. Here, we show that CXCR4 nuclear localization is more likely to occur in RCC tissues, especially in metastases, and is associated with poor prognosis. CXCR4 nuclear localization requires its nuclear localization sequence (NLS, residues 146-RPRK-149). After the mutation of NLS in CXCR4, CXCR4 nuclear localization in RCC cells is lost. Nuclear localization of CXCR4 promoted RCC tumorigenicity both in vitro and in vivo. Mechanistically, we found that CXCR4 and hypoxia-inducible factor-1 alpha (HIF-1 alpha) colocalized in RCC cells and interacted with each other. Moreover, CXCR4 nuclear localization promoted nuclear accumulation of HIF-1 alpha, thereby promoting the expression of genes downstream of HIF-1 alpha. Reciprocally, nuclear HIF-1 alpha promoted CXCR4 transcription, thus forming a feed-forward loop. Subcellular CXCR4 and HIF-1 alpha expression levels were independent adverse prognostic factors and could be combined with TNM stage to generate a predictive nomogram of the clinical outcome of patients with RCC. Therefore, our findings indicate that CXCR4 nuclear translocation plays a critical role in RCC metastasis and may serve as a prognostic biomarker and potential therapeutic target.