CXCR7 promotes migration and invasion in head and neck squamous cell carcinoma by upregulating TGF-β1/Smad2/3 signaling

Abstract

The chemokine receptor CXCR7 has been suggested to play important roles in the progression of several types of cancers. However, few studies have investigated the biological roles of CXCR7 in head and neck squamous cell carcinoma (HNSCC). CXCR7 expression and its clinical implications were examined in 103 HNSCC tissues using immunohistochemistry (IHC). The biological roles and mechanisms of CXCR7-mediated signaling pathways were investigated in HNSCC cells through CXCR7 overexpression in vitro and in vivo. High expression of CXCR7 was significantly associated with tumor size (P = 0.007), lymph node metastasis (P = 0.004), and stage (P = 0.020) in HNSCC. Overexpression of CXCR7 in HNSCC cells enhanced cell migration and invasion in vitro and promoted lymph node metastasis in vivo. CXCR7 also induced epithelial-mesenchymal transition through PI3K/AKT. CXCR7 increased secretion of transforming growth factor-β1 (TGF-β1) and promoted EMT through phosphorylated Smad2/3. Taken together, our results provide functional and mechanistic roles of CXCR7 as a master regulator of oncogenic TGF-β1/Smad2/3 signaling in HNSCC, suggesting that CXCR7 might be a therapeutic target for the treatment of HNSCC.Head and neck squamous cell cancer (HNSCC) constitutes a heterogeneous group of cancers. HNSCC is an epithelial malignancy with primary sites in the lip, oral cavity, pharynx, larynx, and paranasal sinuses 1,2 . High cure rates are achieved for localized HNSCC using surgery, radiation, and chemoradiation. However, recurrence after curative resection is common, and survival rates for recurrent/metastatic disease remain poor, with a 10% 5-year overall survival rate 3 . Therefore, an understanding of the molecular mechanisms of cancer progression is necessary to advance the treatment of HNSCC.In the tumor microenvironment, chemokine signaling systems play critical roles in tumor progression, invasion, migration, and metastasis 4 . Chemokines and chemokine receptors are differentially expressed in various malignant tumors 5,6 . Growing evidence shows that CXCR7 plays a crucial role in the development of tumors 7 . Furthermore, upregulation of CXCR7 serves as an oncogene in various cancers, such as breast and lung cancer 5,8 .Tumors metastasize through decreased cell adhesion, basement membrane perforation, migration by circulation, immune escape, and formation of colonies at distant sites 9 . Epithelial-mesenchymal transition (EMT) is essential for initiation and progression of metastasis 10,11 . Transforming growth factor (TGF)-β signaling is known to induce EMT through various intracellular messengers. Recent studies have shown that TGF-β promotes tumor progression and metastasis by regulating chemokines or chemokine receptors in the tumor MethodsPatients and tumor samples. A total of 103 HNSCC tissues were recruited from the Chungnam National University Hospital. All samples used in the study were approved by the ethics committee of Chungnam National University Hospital. Written informed consent was obtained from all the patients. ...

SOX4 promotes the growth and metastasis of breast cancer

“…The activation of CXCR7 by its ligand CXCL12 could promote cell migration, angiogenesis, tumorigenesis, invasion, metastasis and anti-apoptosis [25]. CXCR7 is considered to be an EMT-related gene and is highly expressed in various cancer cells [26][27][28][29][30][31]. It was shown to be involved in the regulation of several pathways in cancer cells such as TGF-β1/Smad2/3 [30], PI3K/Akt [32] and β-arrestin [33] signaling pathways.…”

SOX4 promotes the growth and metastasis of breast cancer

“…EMT enhances cell motility and helps the release of breast cancer cells from the primary tumor and the establishment of metastatic colonies at distant sites [40]. Previous studies have reported that CXCR7 promotes EMT by upregulating TGF-β1 [28][29][30]. We determined the expression levels of EMT-related genes in SOX4-expressing cells and found that the expression of three mesenchyme markers Vimentin, N-cadherin, and Fibronectin were upregulated, and that of the epithelial marker E-cadherin was downregulated.…”

“…The activation of CXCR7 by its ligand CXCL12 could promote cell migration, angiogenesis, tumorigenesis, invasion, metastasis and antiapoptosis [24]. CXCR7 is considered to be an EMT-related gene and is highly expressed in various cancer cells [25][26][27][28][29][30]. However, the effect of CXCR7 on distant metastasis of breast cancer remains unclear.…”

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