BACKGROUND Carcinoma cells shift between epithelial and mesenchymal phenotypes during cancer progression, as defined by surface presentation of the cell-cell cohesion molecule E-cadherin, affecting dissemination, progression and therapy responsiveness. Concomitant with the loss of E-cadherin during the mesenchymal transition, the predominant receptor isoform for ELR-negative CXC ligands shifts from CXCR3-B to CXCR3-A which turns this classical G-protein coupled receptor from an inhibitor to an activator of cell migration, thus promoting tumor cell invasiveness. We proposed that CXCR3 was not just a coordinately changed receptor but actually a regulator of the cell phenotype. METHODS Immunoblotting, immunofluorescence, quantitative real-time PCR and flow cytometry assays investigated the expression of E-cadherin and CXCR3 isoforms. Intrasplenic inoculation of human prostate cancer (PCa) cells with spontaneous metastasis to the liver analyzed E-cadherin and CXCR3-B expression during cancer progression in vivo. RESULTS We found reciprocal regulation of E-cadherin and CXCR3 isoforms. E-cadherin surface expression promoted CXCR3-B presentation on the cell membrane, and to a lesser extent increased its mRNA and total protein levels. In turn, forced expression of CXCR3-A reduced E-cadherin expression level, whereas CXCR3-B increased E-cadherin in PCa. Meanwhile, a positive correlation of E-cadherin and CXCR3-B expression was found both in experimental PCa liver micro-metastases and patients' tissue. CONCLUSIONS CXCR3-B and E-cadherin positively correlated in vitro and in vivo in PCa cells and liver metastases, whereas CXCR3-A negatively regulated E-cadherin expression. These results suggest that CXCR3 isoforms may play important roles in cancer progression and dissemination via diametrically regulating tumor's phenotype.

中文翻译：

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E-钙粘着蛋白和特定的CXCR3亚型的表达在前列腺癌中相互影响。

背景技术癌细胞在癌症进展过程中在上皮和间充质表型之间转移，这由细胞-细胞粘附分子E-钙粘着蛋白的表面表现所定义，影响了扩散，进展和治疗反应性。与间充质转化过程中E-钙黏着蛋白的丧失相伴，ELR阴性CXC配体的主要受体亚型从CXCR3-B转变为CXCR3-A，这使这种经典的G蛋白偶联受体从抑制剂转变为细胞迁移的激活剂，从而促进肿瘤细胞的侵袭性。我们提出，CXCR3不仅是协调改变的受体，而且实际上是细胞表型的调节剂。方法免疫印迹，免疫荧光，实时荧光定量PCR和流式细胞仪检测了E-钙粘蛋白和CXCR3亚型的表达。脾内接种自发转移至肝脏的人前列腺癌（PCa）细胞分析了体内癌症进展过程中E-钙黏着蛋白和CXCR3-B的表达。结果我们发现E-钙粘蛋白和CXCR3亚型的相互调节。E-钙粘着蛋白的表面表达促进了CXCR3-B在细胞膜上的表达，并在较小程度上增加了其mRNA和总蛋白水平。反过来，在PCa中强制表达CXCR3-A会降低E-钙黏着蛋白的表达水平，而CXCR3-B会增加E-钙黏着蛋白的表达。同时，在实验性PCa肝微转移和患者组织中均发现E-cadherin与CXCR3-B表达呈正相关。结论CXCR3-B和E-钙粘蛋白在PCa细胞和肝转移体内和体外呈正相关，而CXCR3-A负调控E-钙粘蛋白的表达。