Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China.
Department of Gastroenterology, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cell Death Differ. 2017 Sep;24(9):1577-1587. doi: 10.1038/cdd.2017.87. Epub 2017 Jun 2.
Familiar clustering of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) has been frequently reported. However, limited information is available about the underlying molecular mechanisms in HBV-related HCC patients with family history of HCC. In our previous study, Agilent miRNA Base 16.0 microarray showed miRNA profiles of the plasma of HBV-related HCC patients who had a family history of HCC. This study aims to explore the expression, function, and mechanisms of miR-3188 in HCC that might provide novel insights into the role of family history on the risk of HCC. The expression levels of miR-3188 were markedly overexpressed in HCC tissues, HBV transgenic mice, and HepG2.215 cells. We knocked out miR-3188 in HCC cell lines using the CRISPR/Cas9 system, and demonstrated that miR-3188 knockout (KO) suppressed cell growth, migration, and invasion, and inhibited xenografts tumor growth in nude mice. Next, we determined that miR-3188 KO exerts antitumor functions by directly repressing ZHX2. It has been reported that HBV X protein (HBx) plays a critical role in HBV-related HCC, promoting CREB-mediated activation of miR-3188 and activation of Notch signaling through repressing ZHX2. Finally, we verified that ZHX2 functions as a transcriptional repressor to Notch1 via interaction with NF-YA. Our data demonstrate that the HBx-miR-3188-ZHX2-Notch1 signaling pathway plays an important role in the pathogenesis and progression of HBV-related HCC with family history of HCC. These findings have important implications for identifying new therapeutic targets in HBV-related HCC.
乙型肝炎病毒（HBV）相关肝细胞癌（HCC）的常见聚集已被频繁报道。然而，关于有 HCC 家族史的 HBV 相关 HCC 患者的潜在分子机制的信息有限。在我们之前的研究中，Agilent miRNA Base 16.0 微阵列显示了有 HCC 家族史的 HBV 相关 HCC 患者血浆中的 miRNA 图谱。本研究旨在探索 miR-3188 在 HCC 中的表达、功能和机制，这可能为家族史对 HCC 风险的作用提供新的见解。miR-3188 在 HCC 组织、HBV 转基因小鼠和 HepG2.215 细胞中的表达水平明显上调。我们使用 CRISPR/Cas9 系统敲除 HCC 细胞系中的 miR-3188，证明 miR-3188 敲除（KO）抑制细胞生长、迁移和侵袭，并抑制裸鼠异种移植肿瘤生长。接下来，我们确定 miR-3188 KO 通过直接抑制 ZHX2 发挥抗肿瘤作用。据报道，HBV X 蛋白（HBx）在 HBV 相关 HCC 中起关键作用，通过抑制 ZHX2 促进 CREB 介导的 miR-3188 激活和 Notch 信号通路激活。最后，我们验证了 ZHX2 通过与 NF-YA 相互作用作为 Notch1 的转录抑制因子发挥作用。我们的数据表明，HBx-miR-3188-ZHX2 Notch1 信号通路在有 HCC 家族史的 HBV 相关 HCC 的发病机制和进展中起重要作用。这些发现对确定 HBV 相关 HCC 的新治疗靶点具有重要意义。
