Department of Functional Genomics, University of Science and Technology, Daejeon, 34141, Republic of Korea; Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea; Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan, 570-450, Republic of Korea.
Biochem Biophys Res Commun. 2019 Jan 1;508(1):275-281. doi: 10.1016/j.bbrc.2018.11.070. Epub 2018 Nov 26.
Precise cell cycle regulation is critical to prevent aberrant cell proliferation and cancer progression. Cks1 was reported to be an essential accessory factor for SCF, the ubiquitin ligase that targets p27 for proteasomal degradation; these actions drive mammalian cell transition from G1 to S phase. In this study, we investigated the role played by Cks1 in the growth and progression of human hepatocellular carcinoma (HCC) cells. Silencing Cks1 expression abrogated osteopontin (OPN) expression in a p27-dependent manner in Huh7 HCC cells. OPN increased the proliferation, migration and invasion of Huh7 cells. Pharmacological inhibitor studies demonstrated that ERK1/2 signaling is responsible mainly for Cks1-mediated OPN expression. Cks1 appears to regulate ERK1/2 signaling through the expression of dual-specificity phosphatase 16 (DUSP16) because both Cks1 knockdown, which leads to DUSP16 upregulation, and DUSP16 overexpression decreased ERK1/2 phosphorylation and the resulting OPN expression. The same is true for the Cks1-mediated increases in p27, suggesting that Cks1 regulates OPN expression through activating ERK1/2 signaling either by suppressing DUSP16 expression or by a p27-dependent mechanism. Cks1 and OPN expression levels were significantly higher, but DUSP16 expression levels were significantly lower in HCC tissues than in normal liver tissues. Both Cks1 and OPN expression were negatively correlated with DUSP16 expression, whereas Cks1 expression was positively correlated with OPN expression. Moreover, combined panels for the expression levels of Cks1, DUSP16 and OPN showed significant prognostic power for the risk assessment of HCC patient overall survival. In conclusion, our data propose a novel function for Cks1 as a tumor promoter through the expression of the strongly oncogenic protein OPN in HCC.
精确的细胞周期调控对于防止异常细胞增殖和癌症进展至关重要。有报道称，Cks1 是 SCF 的必需辅助因子，SCF 是一种泛素连接酶，可靶向 p27 进行蛋白酶体降解；这些作用促使哺乳动物细胞从 G1 期过渡到 S 期。在本研究中，我们研究了 Cks1 在人肝细胞癌（HCC）细胞生长和进展中的作用。沉默 Cks1 表达以 p27 依赖性方式在 Huh7 HCC 细胞中阻断骨桥蛋白（OPN）的表达。OPN 增加了 Huh7 细胞的增殖、迁移和侵袭。药理学抑制剂研究表明，ERK1/2 信号主要负责 Cks1 介导的 OPN 表达。Cks1 似乎通过双特异性磷酸酶 16（DUSP16）的表达来调节 ERK1/2 信号，因为 Cks1 敲低导致 DUSP16 上调，以及 DUSP16 过表达均降低了 ERK1/2 磷酸化和由此产生的 OPN 表达。这同样适用于 Cks1 介导的 p27 增加，表明 Cks1 通过激活 ERK1/2 信号来调节 OPN 表达，或者通过抑制 DUSP16 表达，或者通过 p27 依赖性机制。与正常肝组织相比，HCC 组织中 Cks1 和 OPN 的表达水平显著升高，而 DUSP16 的表达水平显著降低。Cks1 和 OPN 的表达与 DUSP16 的表达呈负相关，而 Cks1 的表达与 OPN 的表达呈正相关。此外，Cks1、DUSP16 和 OPN 的表达水平联合图谱对 HCC 患者总生存风险评估具有显著的预后能力。总之，我们的数据提出了 Cks1 的一个新功能，即通过在 HCC 中表达强烈致癌蛋白 OPN 作为肿瘤促进剂。
