Nantong Rich Hospital, Nantong 226001, Jiangsu Province, People's Republic of China.
Department of Respiratory Medicine, Affiliated Xing Tai People Hospital of Hebei Medical University, Xingtai, 054000, Hebei Province, People's Republic of China; Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong University, Nantong 226001, Jiangsu Province, People's Republic of China.
Hum Pathol. 2018 Feb;72:80-90. doi: 10.1016/j.humpath.2017.09.016. Epub 2017 Nov 8.
NKD2 is a member of the Naked cuticle (Nkd) protein family and functions as a negative regulator of the Wnt signaling pathway. We investigated the prognostic value of NKD2 expression in hepatocellular carcinoma (HCC). Western blot and immunohistochemical analyses revealed that NKD2 was significantly downregulated in HCC specimens compared with adjacent nontumorous tissues. Next, we found that NKD2 expression correlated significantly with several clinicopathologic features, such as tumor grade, tumor size, and Ki-67 expression. Univariate and multivariate analyses demonstrated that NKD2 was an independent prognostic factor for the survival of HCC patients. In particular, Kaplan-Meier survival curves suggested that low NKD2 was statistically associated with poor overall survival. Furthermore, serum refeeding of cultured HCC cells led to impaired amounts of NKD2 and induced HepG2 and Huh7 cells to transition from the G to the S phase. Small interfering RNA-mediated depletion of NKD2 in LO2 hepatocytes caused accelerated cell growth. To further clarify the role of NKD2 in cell cycle progression, a Flag-tagged NKD2 construct was used to overexpress NKD2 exogenously in Huh7 cells. These results showed that overexpression of NKD2 induced G-phase cell cycle arrest. Reduced expression of NKD2 correlated with hyperactivation of the Wnt/β-catenin pathway and doxorubicin resistance in HCC cells. On the basis of these findings, we conclude that NKD2 may be a novel prognostic marker and therapeutic target in HCC.
NKD2 是 Naked cuticle（Nkd）蛋白家族的成员，作为 Wnt 信号通路的负调节剂发挥作用。我们研究了 NKD2 表达在肝细胞癌（HCC）中的预后价值。Western blot 和免疫组织化学分析显示，与相邻非肿瘤组织相比，NKD2 在 HCC 标本中显著下调。接下来，我们发现 NKD2 表达与几种临床病理特征显著相关，如肿瘤分级、肿瘤大小和 Ki-67 表达。单因素和多因素分析表明，NKD2 是 HCC 患者生存的独立预后因素。特别是，Kaplan-Meier 生存曲线表明，低 NKD2 与总生存率差统计学相关。此外，培养的 HCC 细胞的血清再喂养导致 NKD2 的含量受损，并诱导 HepG2 和 Huh7 细胞从 G 期过渡到 S 期。在 LO2 肝细胞中用小干扰 RNA 耗尽 NKD2 会导致细胞生长加速。为了进一步阐明 NKD2 在细胞周期进程中的作用，使用 Flag 标记的 NKD2 构建体在 Huh7 细胞中外源性过表达 NKD2。这些结果表明，过表达 NKD2 诱导 G 期细胞周期停滞。NKD2 的表达减少与 HCC 细胞中 Wnt/β-catenin 通路的过度激活和阿霉素耐药相关。基于这些发现，我们得出结论，NKD2 可能是 HCC 的一种新的预后标志物和治疗靶点。
