Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, China.
Department of Hepatobiliary Surgery, General Hospital, Ningxia Medical University, Yinchuan, 750001, China.
J Exp Clin Cancer Res. 2017 Sep 4;36(1):117. doi: 10.1186/s13046-017-0576-3.
The overall response rate of hepatocellular carcinoma (HCC) to chemotherapy is poor. In our previous study, oxaliplatin-resistant HCC is found to exhibit an enhanced stemness, and increased levels of CCN2 and LRP6, while the role of CCN2 and LRP6 in the prognosis of HCC patients, and the interaction regulation mechanism between CCN2 and LRP6 are still unclear.
The expression levels of CCN2 and LRP6 were detected in large cohorts of HCCs, and functional analyses of CCN2 and LRP6 were performed both in vitro and in vivo. The roles of cell surface heparin sulfate proteoglycans (HSPGs) in the mutual regulatory between CCN2 and LRP6 were verified in HCC, and the interventions of low molecular weight heparin sodium (LMWH) were explored.
CCN2 and LRP6 were overexpressed in HCCs, and the CCN2 and LRP6 levels were positively associated with the malignant phenotypes and poor prognosis of HCCs. LRP6 could significantly upregulate the expression of CCN2. Meanwhile, CCN2 was able to enhance malignant phenotype of HCC cells in a dose-dependent manner through binding with LRP6; and knock-down of LRP6 expression, perturbation of HSPGs, co-incubation of CCN2 with LMWH could significantly block the adhesion of CCN2 to LRP6. LMWH enhanced the therapeutic effect of oxaliplatin on HCC with a high CCN2 expression.
CCN2 plays a promoting role in HCC progression through activating LRP6 in a HSPGs-dependent manner. Heparin in combination with chemotherapy has a synergic effect and could be a treatment choice for HCCs with a high CCN2 expression.
肝细胞癌（HCC）对化疗的总体反应率较差。在我们之前的研究中，发现奥沙利铂耐药的 HCC 表现出增强的干性，以及 CCN2 和 LRP6 水平的增加，而 CCN2 和 LRP6 在 HCC 患者预后中的作用以及它们之间的相互调控机制仍不清楚。
在大量 HCC 样本中检测了 CCN2 和 LRP6 的表达水平，并在体外和体内进行了 CCN2 和 LRP6 的功能分析。在 HCC 中验证了细胞表面硫酸乙酰肝素蛋白聚糖（HSPGs）在 CCN2 和 LRP6 之间相互调节中的作用，并探讨了低分子量肝素钠（LMWH）的干预作用。
CCN2 和 LRP6 在 HCC 中过度表达，CCN2 和 LRP6 的水平与 HCC 的恶性表型和不良预后呈正相关。LRP6 可显著上调 CCN2 的表达。同时，CCN2 能够通过与 LRP6 结合以剂量依赖的方式增强 HCC 细胞的恶性表型；敲低 LRP6 表达、干扰 HSPGs、CCN2 与 LMWH 共孵育均可显著阻断 CCN2 与 LRP6 的结合。LMWH 增强了 CCN2 表达水平高的 HCC 对奥沙利铂的治疗效果。
CCN2 通过 HSPGs 依赖性激活 LRP6 在 HCC 进展中发挥促进作用。肝素联合化疗具有协同作用，可作为 CCN2 表达水平高的 HCC 的治疗选择。
