Reduced expression of Nrdp1 predicts a poor prognosis in human hepatocellular carcinoma.
Reduced expression of Nrdp1 predicts a poor prognosis in human hepatocellular carcinoma.
复制标题
DOI：
10.2147/ott.s160638
复制
发表时间：
2018
影响因子：
4
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Shao X;Lu Q;Wang G;Huang W;Yang L;Chen Z
肝细胞癌（HCC）是一种侵袭性肝癌，患者的生存率特别低。缺乏靶向分子治疗，目前的治疗一般仅限于手术切除或肝移植。 ErbB 受体家族的过度表达和异常信号传导与 HCC 有关，但 ErbB 过度表达的机制尚不清楚。在这项研究中，我们研究了神经调节蛋白受体降解蛋白 1 (Nrdp1)（ErbB3 蛋白稳定性的调节因子）在 HCC 进展中的潜在作用。我们使用蛋白质印迹分析比较了 Nrdp1 在各种 HCC 细胞系以及 8 对肿瘤和肿瘤周围组织样本中的表达。使用细胞计数 Kit-8 (ccK-8) 测定和细胞周期分析，确定小干扰 RNA (siRNA) 诱导 Nrdp1 敲低之前和之后增殖程度的变化。在 89 名 HCC 患者的标本中确定了 Nrdp1 表达与预后之间的相关性。与邻近健康组织相比，HCC 组织中 Nrdp1 的表达显着降低。较高的 Nrdp1 表达对应于较低的最大肿瘤大小（χ2，P<0.05）、较低的组织学分级（χ2，P<0.05）以及 Kaplan-Meier 估计的较高生存率（P<0.05）。 Nrdp1 表达较高也对应于细胞增殖标志物 Ki-67 表达的减少（Spearman，r2=0.734；P<0.05）。 Nrdp1 在血清饥饿的 HepG2 癌细胞中积累，并在重新喂养后表达逐渐降低。此外，通过 siRNA 消除健康 L02 细胞中的 Nrdp1 会导致细胞增殖增强，并导致更多比例的细胞处于 S 期。我们的研究结果表明 Nrdp1 在 HCC 肿瘤发生中具有抑制作用，我们提出 Nrdp1 可以作为 HCC 的预后生物标志物，并作为 HCC 治疗的潜在治疗靶点。
Hepatocellular carcinoma (HCC) is an aggressive form of liver cancer with particularly poor survival rates for patients. Targeted molecular therapies are lacking, and current treatment is generally limited to surgical resection or liver transplantation. Overexpression and aberrant signaling of the ErbB family of receptors has been implicated in HCC, but the mechanisms underlying ErbB overexpression are unclear. In this study, we investigated the potential role of neuregulin receptor degradation protein-1 (Nrdp1), a regulator of ErbB3 protein stability, in HCC progression. We compared the expression of Nrdp1 in various HCC cell lines and in 8 pairs of tumor and peritumor tissue samples using Western blot analysis. Changes in the degree of proliferation were determined before and after small interfering RNA (siRNA)-induced knockdown of Nrdp1 using a cell counting Kit-8 (ccK-8) assay and cell-cycle analysis. The correlation between Nrdp1 expression and prognosis was determined in specimens of 89 HCC patients. Nrdp1 expression is significantly reduced in HCC tissues compared with adjacent healthy tissues. Higher Nrdp1 expression corresponds to lower maximal tumor size (χ2, P<0.05), lower histological grade (χ2, P<0.05), and higher survival rates by Kaplan–Meier estimate (P<0.05). Higher Nrdp1 expression also corresponds to reduced expression of Ki-67, a marker of cell proliferation (Spearman, r2=0.734; P<0.05). Nrdp1 accumulates in serum-starved HepG2 cancer cells and progressively decreases in expression after re-feeding. Furthermore, depletion of Nrdp1 in healthy L02 cells by siRNA results in enhanced cell proliferation and a greater proportion of cells in S phase. Our findings suggest an inhibitory role for Nrdp1 in HCC tumorigenesis, and we propose that Nrdp1 may serve as a prognostic biomarker for HCC and as a potential therapeutic target for the treatment of HCC.