The atypical chemokine receptor, CXCR7, has been shown to play an important role in the progression of several types of cancer. However, there have been few reports on the biological role of CXCR7 in head and neck squamous cell carcinoma (HNSCC). In this study, we investigated the functional role of CXCR7 and the underlying molecular mechanism of disease progression in HNSCC.
We examined the association between CXCR7 expression and clinicopathological characteristics in 103 cases of HNSCC using tissue microarrays by immunohistochemical staining. The biological roles of CXCR7 and CXCR7-mediated signaling pathways were investigated in HNSCC cell through CXCR7 overexpression and treatment of SDF-1α, a major ligand of CXCR7, as well as knockdown of CXCR7 in vitro and in vivo.
CXCR7 was differentially expressed in human HNSCC tissues. High expression of CXCR7 was significantly related to depth of tumor invasion (P = 0.007), lymph node metastasis (P = 0.004), and tumor stage (P = 0.02). Overexpression of CXCR7 dramatically enhanced cell migration and invasion in HNSCC cells in vitro, and promoted lymph node metastasis in vivo. CXCR7 knockdown using siRNA in HNSCC cells recovered the cell migratory and invasive behavior of HNSCC cells. CXCR7 overexpression also induced the epithelial-mesenchymal transition. Vimentin, Slug, and Twist were increased but E-cadherin and Ep-CAM were decreased by CXCR7 expression. Akt phosphorylation and Smad2 signaling activation were induced in HNSCC cells with CXCR7 overexpression. Treatment with a PI3K inhibitor reduced Slug and Twist levels while suppression of Smad2 signaling by siRNA reduced Akt phosphorylation, as well as Slug and Twist. Furthermore, inhibition of Smad2 decreased tumor cell migration and invasion in HNSCC.
CXCR7 expression was associated with an aggressive tumor behavior in HNSCC. CXCR7 contributed to cell migration and invasion of HNSCC cell through the Smad2/Akt signaling axis in vitro, and was involved in lymph node metastasis in vivo, suggesting that CXCR7 might be a therapeutic target for the treatment of HNSCC.
Clinical trial identification
Legal entity responsible for the study
Hyo Jin Lee.
Cancer Research Institute of CNU.
All authors have declared no conflicts of interest.