Expression of the CXCL12/CXCR4 and CXCL16/CXCR6 axes in cervical intraepithelial neoplasia and cervical cancer

Abstract

The chemokine CXCL12 is highly expressed in gynecologic tumors and is widely known to play a biologically relevant role in tumor growth and spread. Recent evidence suggests that CXCL16, a novel chemokine, is overexpressed in inflammation-associated tumors and mediates pro-tumorigenic effects of inflammation in prostate cancer. We therefore analyzed the expression of CXCL12 and CXCL16 and their respective receptors CXCR4 and CXCR6 in cervical intraepithelial neoplasia (CIN) and cervical cancer and further assessed their association with clinicopathologic features and outcomes. Tissue chip technology and immunohistochemistry were used to analyze the expression of CXCL12, CXCR4, CXCL16, and CXCR6 in healthy cervical tissue (21 cases), CIN (65 cases), and cervical carcinoma (60 cases). The association of protein expression with clinicopathologic features and overall survival was analyzed. These four proteins were clearly detected in membrane and cytoplasm of neoplastic epithelial cells, and their distribution and intensity of expression increased as neoplastic lesions progressed through CIN1, CIN2, and CIN3 to invasive cancer. Furthermore, the expression of CXCR4 was associated significantly with the histologic grade of cervical carcinoma, whereas the expression of CXCR6 was associated significantly with lymph node metastasis. In Kaplan-Meier analysis, patients with high CXCR6 expression had significantly shorter overall survival than did those with low CXCR6 expression. The elevated co-expression levels of CXCL12/CXCR4 and CXCL16/CXCR6 in CIN and cervical carcinoma suggest a durative process in cervical carcinoma development. Moreover, CXCR6 may be useful as a biomarker and a valuable prognostic factor for cervical cancer.

Virus proteins similar to human proteins as possible disturbance on human pathways

“…It has been studied that the expression of CXCR6 was associated significantly with lymph node metastasis. In Kaplan-Meier analysis, patients with high CXCR6 expression had significantly lower overall survival than did those with low CXCR6 expression (Huang et al 2013). The elevated co-expression levels of CXCL12/ CXCR4 and CXCL16/CXCR6 in cervical intraepithelial neoplasia (CIN) and cervical carcinoma suggest a durative process in cervical carcinoma evolution, and CXCR6 may be useful as a biomarker and a valuable prognostic factor for cervical cancer (Huang et al 2013).…”

“…In Kaplan-Meier analysis, patients with high CXCR6 expression had significantly lower overall survival than did those with low CXCR6 expression (Huang et al 2013). The elevated co-expression levels of CXCL12/ CXCR4 and CXCL16/CXCR6 in cervical intraepithelial neoplasia (CIN) and cervical carcinoma suggest a durative process in cervical carcinoma evolution, and CXCR6 may be useful as a biomarker and a valuable prognostic factor for cervical cancer (Huang et al 2013). According to our hypothesis, the high expression of CXCR6 in the cervical cancer process could be inferred as an advantage of the HPV infection, because more CXCR6 might be perturbed by viral oncoproteins easily and lead to tumor.…”

Role of CXCR7 and Effects on CXCL12 in SiHa Cells and Upregulation in Cervical Squamous Cell Carcinomas in Uighur Women

“…Chemokines and their receptors are widely influences the development of primary tumors and metastases (Balkwill, 2004). The significance of the CXCL12/CXCR4 axis in cervical cancer invasion and metastasis has been widely investigated (Huang et al, 2013). In addition to CXCR4, CXCR7 was a recently identified and as a second, high-affinity receptor for CXCL12, which was originally cloned on the basis of its homology with conserved domains of G-protein coupled seven-span transmembrane receptors (Sun et al, 2010;Zabel et al, 2011).…”

“…In addition to CXCR4, CXCR7 was a recently identified and as a second, high-affinity receptor for CXCL12, which was originally cloned on the basis of its homology with conserved domains of G-protein coupled seven-span transmembrane receptors (Sun et al, 2010;Zabel et al, 2011). This receptor is highly expressed by a variety of cancers, including breast, liver, and lung (Heinrich et al, 2012;Xue et al, 2013;Roy et al, 2014), as well as cervical cancer (Huang et al, 2013).…”

“…CXCR4 and CXCR7 are two receptors of CXCL12 that have been identified. several authors have investigated CXCR4 expression, its function and prognostic impact in cervical cancer, inhibition of the CXCR4 receptor by mac239 has shown an anti-proliferative effect in cervical cancer (Cai et al, 2012;Huang et al, 2013;Wen et al, 2013).…”