Vaccinia-related kinase 1 promotes hepatocellular carcinoma by controlling the levels of cell cycle regulators associated with G1/S transition.
Vaccinia-related kinase 1 promotes hepatocellular carcinoma by controlling the levels of cell cycle regulators associated with G1/S transition.
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DOI：
10.18632/oncotarget.4967
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发表时间：
2015-10-06
期刊：
影响因子：
--
通讯作者：
Choi KY
中科院分区：
文献类型：
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作者：
Lee N;Kwon JH;Kim YB;Kim SH;Park SJ;Xu W;Jung HY;Kim KT;Wang HJ;Choi KY
我们确定了牛痘相关激酶1（VRK 1）在肝细胞癌（HCC）进展中的特定作用，并评估了其治疗和预后潜力。VRK 1水平在HCC细胞系中显著高于正常肝细胞系，并且在HCC中高于非肿瘤组织。VRK 1敲低抑制SK-Hep 1，SH-J1和Hep 3B细胞的增殖;此外，VRK 1的消耗抑制体内HCC肿瘤的生长。我们还发现，VRK 1敲除通过减少细胞周期蛋白D1和p-Rb而上调p21和p27，增加了G1期阻滞细胞的数量，VRK 1敲除下调了CREB的磷酸化，CREB是一种调节CCND 1的转录因子。此外，我们发现毛地黄黄酮，一种VRK 1抑制剂，在体外和体内抑制HCC生长，并且VRK 1的异常表达与HCC的不良预后特征相关。高水平的VRK 1与较短的总生存期和无病生存期以及较高的复发率相关。综上所述，我们的研究结果表明VRK 1可能通过控制与G1/S转换相关的细胞周期调节因子的水平而起肿瘤促进剂的作用，并可能作为HCC的治疗靶点和/或预后生物标志物。
We identified the specific role of vaccinia-related kinase 1 (VRK1) in the progression of hepatocellular carcinoma (HCC) and evaluated its therapeutic and prognostic potential. VRK1 levels were significantly higher in HCC cell lines than a normal hepatic cell line, and were higher in HCC than non-tumor tissue. VRK1 knockdown inhibited the proliferation of SK-Hep1, SH-J1 and Hep3B cells; moreover, depletion of VRK1 suppressed HCC tumor growth in vivo. We also showed that VRK1 knockdown increased the number of G1 arrested cells by decreasing cyclin D1 and p-Rb while upregulating p21 and p27, and that VRK1 depletion downregulated phosphorylation of CREB, a transcription factor regulating CCND1. Additionally, we found that luteolin, a VRK1 inhibitor, suppressed HCC growth in vitro and in vivo, and that the aberrant VRK1 expression correlated with poor prognostic features of HCC. High levels of VRK1 were associated with shorter overall and disease-free survival and higher recurrence rates. Taken together, our findings suggest VRK1 may act as a tumor promoter by controlling the level of cell cycle regulators associated with G1/S transition and could potentially serve as a therapeutic target and/or prognostic biomarker for HCC.