Department of Gastroenterology, Taizhou People's Hospital, Taizhou, China.
Department of Pathology, Xishan People's Hospital of Wuxi City, Wuxi, China.
Cancer Sci. 2022 Oct;113(10):3390-3404. doi: 10.1111/cas.15498. Epub 2022 Aug 1.
Although angiogenesis is a critical event in hepatocellular carcinoma (HCC), and this process provides the tumor with sufficient oxygen and nutrients, the precise molecular mechanism by which it occurs is not fully understood. NEDD4 binding protein 3 (N4BP3) was identified in this study as a novel pro-angiogenic factor in HCC cell lines and tissues. We discovered that N4BP3 was significantly expressed in HCC and that its level of expression was positively correlated with the density of tumor microvessels in HCC tissues. Cell biology experiments have shown that N4BP3 knockdown in HCC cells significantly inhibits the formation of complete tubular structures by HUVECs in vitro and HCC angiogenesis in vivo. In HCC cells, overexpression of N4BP3 has the opposite effects. Further cell and molecular biology experiments have revealed that N4BP3 interacts with KAT2B (lysine acetyltransferase 2B), increasing signal transducer and activator of transcription 3 (STAT3) expression by regulating the distribution of acetyl-histone H3 (Lys27) (H3K27ac) in its promoter region. This, in addition, regulates the activity of the STAT3 signaling pathway, which promotes the proliferation of microvessels in HCC and accelerates the malignant process of the tumor. In vivo experiments in nude mice have confirmed our findings, and also suggested that N4BP3 could be a potential target for the treatment of HCC in combination with sorafenib.
尽管血管生成是肝细胞癌（HCC）的一个关键事件，并且这个过程为肿瘤提供了足够的氧气和营养，但它的确切分子机制尚不完全清楚。在本研究中，NEDD4 结合蛋白 3（N4BP3）被鉴定为 HCC 细胞系和组织中的一种新的促血管生成因子。我们发现 N4BP3 在 HCC 中明显表达，其表达水平与 HCC 组织中肿瘤微血管密度呈正相关。细胞生物学实验表明，在 HCC 细胞中敲低 N4BP3 可显著抑制 HUVEC 体外形成完整管状结构和 HCC 血管生成，而 HCC 细胞中 N4BP3 的过表达则具有相反的效果。进一步的细胞和分子生物学实验表明，N4BP3 与 KAT2B（赖氨酸乙酰转移酶 2B）相互作用，通过调节其启动子区域乙酰化组蛋白 H3（Lys27）（H3K27ac）的分布，增加信号转导和转录激活因子 3（STAT3）的表达。这反过来又调节了 STAT3 信号通路的活性，促进了 HCC 中小血管的增殖，并加速了肿瘤的恶性进程。裸鼠体内实验证实了我们的发现，并表明 N4BP3 可能与索拉非尼联合成为治疗 HCC 的潜在靶点。
