Overexpression of Dickkopf-1 predicts poor prognosis for patients with hepatocellular carcinoma after orthotopic liver transplantation by promoting cancer metastasis and recurrence
Overexpression of Dickkopf-1 predicts poor prognosis for patients with hepatocellular carcinoma after orthotopic liver transplantation by promoting cancer metastasis and recurrence
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DOI：
10.1007/s12032-014-0966-8
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发表时间：
2014-07-01
期刊：
影响因子：
3.4
通讯作者：
Qin, Wenxin
中科院分区：
文献类型：
--
作者：
Huang, Yan;Yang, Xinrong;Qin, Wenxin
我们先前的数据表明，Dickkopf - 1（DKK1）与β - 连环蛋白相结合是肝细胞癌（HCC）患者一种新的预后预测因子。然而，DKK1在肝细胞癌复发或转移中的作用及机制仍知之甚少。本研究旨在评估DKK1在原位肝移植（OLT）后肝细胞癌患者肿瘤转移中的作用。在具有不同转移潜能的肝细胞系、肝癌细胞系以及OLT后的肝癌患者中检测DKK1蛋白的表达。通过小干扰RNA介导的方法下调HCCLM3细胞中DKK1的表达后，研究DKK1在细胞侵袭和转移中的作用。利用基因芯片分析两对肝癌细胞中与DKK1相关的差异表达基因。通过Kaplan - Meier和Cox回归分析进一步评估DKK1在148例OLT后的肝癌患者中的预后意义。在高侵袭性肝癌细胞以及疾病复发组的肝癌患者中，DKK1蛋白的表达较高。随着DKK1的下调，HCCLM3细胞在体外表现出侵袭性降低，在体内转移能力下降。DKK1能够调节许多参与与肿瘤进展相关的生物学过程和通路的基因。此外，在临床肝癌样本中，DKK1的过表达与肿瘤微血管密度相关。多变量分析显示，在这组OLT后的肝癌患者中，DKK1是总体生存和累积复发的独立预后指标。总之，DKK1的过表达与OLT后肝细胞癌的侵袭/转移有关，并且DKK1过表达可能是肝癌潜在的分子治疗靶点。
Our previous data had shown that Dickkopf-1 (DKK1) combined with beta-catenin was a novel prognostic predictor for hepatocellular carcinoma (HCC) patients. However, the role and mechanism of DKK1 in HCC recurrence or metastasis remain poorly understand. This study was to assess the role of DKK1 in tumor metastasis for patients with hepatocellular carcinoma after orthotopic liver transplantation (OLT). The expression of DKK1 protein was detected in hepatic cell lines, HCC cell lines, and HCC patients after OLT with different potential of metastasis. After DKK1 expression in the HCCLM3 cells was downregulated by siRNA-mediated approach, the role of DKK1 in cell invasion and metastasis was investigated. cDNA genechip was used to analyze the differential expressed genes related with DKK1 in two pairs of HCC cells. The prognostic significance of DKK1 was further assessed by Kaplan-Meier and Cox regression analyses in 148 HCC patients after OLT. The expression of DKK1 protein was higher in the high-invasive HCC cells and HCC patients of the disease recurrence group. With the down-regulation of DKK1, HCCLM3 cells showed decreased aggressiveness in vitro and lower metastatic ability in vivo. DKK1 could regulate many genes involved in biological processes and pathways related with tumor progression. Furthermore, DKK1 overexpression correlated with tumor microvessel density in clinical HCC samples. Multivariate analysis revealed that DKK1 was an independent prognostic indicator for overall survival and cumulative recurrence in this cohort of HCC patients post-OLT. Collectively, overexpression of DKK1 was implicated in invasion/metastasis of HCC after OLT and DKK1 overexpression may be potential molecular therapeutic targets for liver cancer.