Low Level of Low-Density Lipoprotein Receptor-Related Protein 1 Predicts an Unfavorable Prognosis of Hepatocellular Carcinoma after Curative Resection

BackgroundLow-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor involved in receptor-mediated endocytosis and cell signaling. The aim of this study was to elucidate the expression and mechanism of LRP1 in hepatocellular carcinoma (HCC). MethodsLRP1 expression in 4 HCC cell lines and 40 HCC samples was detected. After interruption of LRP1 expression in a HCC cell line either with specific lentiviral-mediated shRNA LRP1 or in the presence of the LRP1-specific chaperone, receptor-associated protein (RAP), the role of LRP1 in the migration and invasion of HCC cells was assessed in vivo and in vitro, and the expression of matrix metalloproteinase (MMP) 9 in cells and the bioactivity of MMP9 in the supernatant were assayed. The expression and prognostic value of LRP1 were investigated in 327 HCC specimens. ResultsLow LRP1 expression was associated with poor HCC prognosis, with low expression independently related to shortened overall survival and increased tumor recurrence rate. Expression of LRP1 in non-recurrent HCC samples was significantly higher than that in early recurrent samples. LRP1 expression in HCC cell lines was inversely correlated with their metastatic potential. After inhibition of LRP1, low-metastatic SMCC-7721 cells showed enhanced migration and invasion and increased expression and bioactivity of MMP9. Correlation analysis showed a negative correlation between LRP1 and MMP9 expression in HCC patients. The prognostic value of LRP1 expression was validated in the independent data set. ConclusionsLRP1 modulated the level of MMP9 and low level of LRP1 expression was associated with aggressiveness and invasiveness in HCCs. LRP1 offered a possible strategy for tumor molecular therapy.背景：低密度脂蛋白受体相关蛋白1（low-density lipoprotein receptor-related protein 1, LRP1）是一种多功能受体，参与受体介导的内吞作用与细胞信号转导。本研究旨在阐明LRP1在肝细胞癌（hepatocellular carcinoma, HCC）中的表达模式及其作用机制。方法：研究人员检测了4株肝癌细胞系与40份肝癌组织样本中LRP1的表达水平。通过特异性慢病毒介导的短发夹RNA（short hairpin RNA, shRNA）靶向敲低LRP1表达，或使用LRP1特异性伴侣蛋白——受体相关蛋白（receptor-associated protein, RAP）干预其功能，随后分别在体内与体外实验中评估LRP1对肝癌细胞迁移与侵袭能力的调控作用，并检测细胞内基质金属蛋白酶（matrix metalloproteinase, MMP）9的表达水平以及细胞上清液中MMP9的生物活性。此外，本研究还在327份肝癌组织标本中探究了LRP1的表达特征及其预后价值。结果：LRP1低表达与肝癌患者不良预后显著相关，其低表达可作为独立危险因素，与患者总生存期缩短及肿瘤复发率升高密切相关。非复发肝癌样本的LRP1表达水平显著高于早期复发样本。肝癌细胞系中LRP1的表达水平与其转移潜能呈负相关。敲低LRP1后，低转移潜能的SMCC-7721细胞的迁移与侵袭能力显著增强，同时细胞内MMP9的表达水平与上清中MMP9的生物活性均显著升高。相关性分析显示，肝癌患者组织中LRP1与MMP9的表达水平呈显著负相关。LRP1的预后预测价值在独立数据集（independent dataset）中得到了验证。结论：LRP1可通过调控MMP9的表达水平参与肝癌的恶性进展，LRP1低表达与肝癌的侵袭性及不良生物学行为密切相关。LRP1有望成为肝癌分子靶向治疗的潜在靶点，为临床肿瘤治疗提供新的策略。