Differential expression patterns of CXCR3 variants and corresponding CXC chemokines in clear cell ovarian cancers and endometriosis

ObjectivesCarcinogenesis of the ovary is often associated with endometriosis. We previously demonstrated that antitumor chemokine receptor CXCR3 was upregulated both in endometriosis and ovarian cancers. Currently, little is known about the roles of CXCR3 variants in these ovarian diseases. In this study, we investigated the expression of CXCR3 variants and their corresponding ligands in endometriosis and ovarian cancers.MethodsThe expression patterns of CXCR3 variants (CXCR3A, CXCR3B and CXCR3-alt) and their corresponding ligands were investigated by quantitative RT-PCR, Western blot and in situ hybridization in normal ovaries (n = 16), endometriosis (n = 12), and clear cell ovarian cancers (n = 22) including endometriosis-coexisting cases (n = 11).ResultsSequence analysis of purified RT-PCR products confirmed the presence of three CXCR3 variants in human ovaries. Quantitative RT-PCR analysis revealed differential expression patterns of these variants depending on conditions. CXCR3A was upregulated both in endometriosis and cancers. On the other hand, CXCR3-alt was upregulated and CXCR3B was downregulated in cancers compared with endometriosis. The corresponding ligand CXCL11 was upregulated only in the cancers with elevated CXCR3-alt. Another ligand CXCL4 was downregulated in the cancers with suppressed CXCR3B. In situ hybridization demonstrated preferential expression of CXCR3A in cancer cells and infiltrating lymphocytes. CXCR3B and CXCR3-alt were detectable mainly in microvessels.ConclusionsCollective data suggest that differential expression patterns of CXC chemokines and CXCR3 variants are involved in specific inflammatory microenvironment of ovarian cancers. Altered balance of CXCR3 variants may become helpful information for better understanding of the pathogenesis of ovarian cancers arising from endometriosis.

Research highlights
► Expression of CXCR3 variants in ovarian cancers and endometriosis were investigated.
► CXCR3A and CXCR3-alt were upregulated and CXCR3B was downregulated in cancers.
► CXCL4 was also downregulated in cancers, elucidating impaired CXCL4–CXCR3B axis.