Abstract：
Xenotropic and polytropic retrovirus receptor 1 (XPR1) is the only known transporter associated with Pi efflux in mammals, and its impact on tumor progression is gradually being revealed. However, the role of XPR1 in hepatocellular carcinoma (HCC) is unknown. A bioinformatics screen for the phosphate exporter XPR1 was performed in HCC patients. The expression of XPR1 in clinical specimens was analyzed using quantitative real-time PCR, Western blot analysis, and immunohistochemical assays. Knockdown of the phosphate exporter XPR1 was performed by shRNA transfection to investigate the cellular phenotype and phosphate-related cytotoxicity of the Huh7 and HLF cell lines. In vivo tests were conducted to investigate the tumorigenicity of HCC cells xenografted into immunocompromised mice after silencing XPR1. Compared with that in paracancerous tissue, XPR1 expression in HCC tissues was markedly upregulated. High XPR1 expression significantly correlated with poor patient survival. Silencing of XPR1 leads to decreased proliferation, migration, invasion, and colony formation in HCC cells. Mechanistically, knockdown of XPR1 causes an increase in intracellular phosphate levels; mitochondrial dysfunction characterized by reduced mitochondrial membrane potential and adenosine triphosphate levels; increased reactive oxygen species levels; abnormal mitochondrial morphology; and downregulation of key mitochondrial fusion, fission, and inner membrane genes. This ultimately results in mitochondria-dependent apoptosis. These findings reveal the prognostic value of XPR1 in HCC progression and, more importantly, suggest that XPR1 might be a potential therapeutic target.
摘要：
异向性和多向性逆转录病毒受体1（XPR1）是哺乳动物中唯一已知的与Pi外排相关的转运蛋白，其对肿瘤进展的影响正在逐渐显现。然而,XPR1在肝细胞癌(HCC)中的作用尚不清楚.在HCC患者中对磷酸盐出口国XPR1进行了生物信息学筛选。使用实时定量PCR分析临床标本中XPR1的表达,蛋白质印迹分析,和免疫组织化学检测。通过shRNA转染进行磷酸盐输出者XPR1的敲低,以研究Huh7和HLF细胞系的细胞表型和磷酸盐相关的细胞毒性。进行体内测试以研究沉默XPR1后异种移植到免疫受损小鼠中的HCC细胞的致瘤性。与癌旁组织相比，XPR1在HCC组织中的表达明显上调。高XPR1表达与低患者生存率显著相关。沉默XPR1导致增殖减少，迁移,入侵,和肝癌细胞中的集落形成。机械上,敲低XPR1导致细胞内磷酸盐水平增加;线粒体功能障碍特征为线粒体膜电位和三磷酸腺苷水平降低;活性氧水平增加;线粒体形态异常;和关键线粒体融合下调,裂变,和内膜基因。这最终导致线粒体依赖性细胞凋亡。这些发现揭示了XPR1在HCC进展中的预后价值，更重要的是,提示XPR1可能是一个潜在的治疗靶点.
