CXCR7 expression correlates with tumor depth in cutaneous squamous cell carcinoma skin lesions and promotes tumor cell survival through ERK activation

Abstract

The chemokine receptor CXCR7 has been demonstrated to be involved in the development of certain cancers, but its role in cutaneous squamous cell carcinoma (SCC) has not been previously investigated. We seek to determine whether CXCR7 is expressed in human cutaneous SCC skin lesions and SCC cell lines. In addition, we evaluate whether CXCR7 plays a role in SCC cell proliferation, survival and migration and which signalling pathways are involved. Using quantitative RT-PCR to analyse the mRNA expression of 19 different chemokine receptors, we found that CXCR7 was much more highly expressed compared to other chemokine receptors in cutaneous SCC cell lines (HSC-1 and HSC-5). On immunohistochemical staining, CXCR7 was found to be expressed in 70% (28 of 40) of human cutaneous SCC tissue specimens, and its expression correlated with tumor depth >4 mm and cancer stage ≥II. CXCR7 but not CXCR4 protein was expressed on the surface of HSC-1 and HSC-5 cells by flow cytometry. Activation of the CXCR7 receptor by CXCL12 promoted survival of HSC-1 and HSC-5 cells through the ERK pathway, but had no significant effect on cell proliferation or migration. In summary, our findings indicate that CXCR7 is frequently expressed in cutaneous SCC skin lesions and its expression correlates with tumor depth and cancer stage. CXCR7 is the predominant chemokine receptor expressed in SCC cell lines, and activation of CXCR7 by CXCL12 promotes survival of SCC cells through the ERK pathway. These findings provide new insights into the significance of CXCR7 in the pathophysiology of SCC.

Oroxylin A reverses the drug resistance of chronic myelogenous leukemia cells to imatinib through CXCL12/CXCR7 axis in bone marrow microenvironment

“…ERK signaling pathway has been reported to be constitutively activated in leukemia and elevated expression of ERK in leukemia is associated with a poor prognosis [37,38]. Many reports have proved that CXCR7 could affect cancer progression through ERK pathway [12][13][14][15][16]. Nevertheless, the role of ERK pathway in CXCL12/CXCR7 axis in BM microenvironment induced drug resistance is less reported.…”

Irradiance-dependent UVB Photocarcinogenesis

“…Slower progression through S phase of cells with damaged DNA may have contributed to these phenomena. Previously, it has been shown that ERK signaling plays an important role in cutaneous SCC survival and growth252627. Therefore, we next evaluated the expression of ERK signaling in our experimental conditions.…”

“…Normal human keratinocytes were obtained from healthy adult foreskin and cultured as previously described25. The study was approved by the ethics committee of Kaohsiung Medical University Hospital and conducted according to the Declaration of Helsinki.…”

Meta-analysis of CXCR7 Expression Related to Clinical Prognosis in Cancers

“…This study was initiated from the aspect of CXCR7 expression, and its correlation with tumor grade, tumor stage, and lymph node metastasis. In cervical cancer research [30], colorectal cancer research by Xu et al [19] cutaneous squamous cell carcinoma research by Hu et al [21] renal cancer research by Wang et al [26] and gallbladder cancer research by Yao et al [27] all of these studies have consistent results for tumor grade, stage and lymph node metastasis [30][31][32][33][34]. These significant clinicopathological relative factors revealed their roles in tumor development [35][36][37][38][39][40].…”

“…CXCR7, as a recently discovered chemokine receptor, has demonstrated its characteristics in six aspects out of the ten top hallmarks of tumors, including resisting cell death, inducing angiogenesis, sustaining proliferative signaling, activating invasion and metastasis, tumor-promoting inflammation, and cancer-related genes [14,[17][18][19][20][21][22]. Both CXCR4 and CXCR7 are receptors of chemokine CXCL12 and have been reported in multiple tumor types.…”