Institute of Stomatology, Chinese PLA General Hospital, Beijing, China; Department of Oncology, PLA 323 Hospital, Xi'an, Shaanxi, China.
Ultrasound Department, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Exp Cell Res. 2018 Sep 15;370(2):373-382. doi: 10.1016/j.yexcr.2018.06.039. Epub 2018 Jun 30.
ADAM17 is believed to promote tumor development by facilitating both cell proliferation and migration. In this study, we investigated the involvement of ADAM17 and the activation of the integrin pathway in the regulation of the malignant properties of hepatocellular carcinoma cells and tissues. ADAM17 was positively correlated with active integrin β1, which was determined using a human tissue microarray and an N-nitrosodiethylamine-induced HCC mouse model. We found elevated ADAM17 and active integrin β1 levels in HCC tissues compared with adjacent liver tissues, and the active integrin β1 levels were associated with tumor size and TNM grade. High ADAM17 and active integrin β1 levels in tumor tissues were significantly associated with poor survival of HCC patients. RNAi-mediated ADAM17 knockdown and integrin β1 blockade significantly attenuated the migration and invasion of HCC cells, and overexpression of ADAM17 showed the reverse effects. ADAM17 interference attenuated the intrahepatic growth and metastasis of HCC cells in an orthotopic xenograft model. ADAM17-knockdown cells showed diminished levels of active integrin β1, p-FAK, p-AKT, MMP-2 and MMP-9. ADAM17 knockdown significantly attenuated the translocation of the Notch1 intracellular domain into the nucleus, whereas overexpression of the Notch1 intracellular domain rescued the translocation and enhanced the activation of integrin β1. Our data provide evidence for ADAM17 as an important determinant of malignant properties via regulation of integrin β1 activation and Notch1 signaling. Inhibition of ADAM17 may provide viable therapeutic potential for preventing HCC metastasis.
ADAM17 被认为通过促进细胞增殖和迁移来促进肿瘤的发展。在这项研究中，我们研究了 ADAM17 的参与以及整合素途径的激活在调节肝癌细胞和组织的恶性特性中的作用。ADAM17 与活性整合素β1呈正相关，这是用人组织微阵列和 N-亚硝二乙胺诱导的 HCC 小鼠模型确定的。我们发现 HCC 组织中 ADAM17 和活性整合素β1 水平升高，与相邻肝组织相比，并且活性整合素β1 水平与肿瘤大小和 TNM 分级相关。肿瘤组织中高 ADAM17 和活性整合素β1 水平与 HCC 患者的不良生存显著相关。RNAi 介导的 ADAM17 敲低和整合素β1 阻断显著减弱了 HCC 细胞的迁移和侵袭，而过表达 ADAM17 则表现出相反的效果。ADAM17 干扰在原位异种移植模型中减弱了 HCC 细胞的肝内生长和转移。ADAM17 敲低细胞显示活性整合素β1、p-FAK、p-AKT、MMP-2 和 MMP-9 的水平降低。ADAM17 敲低显著减弱了 Notch1 细胞内结构域向核内的易位，而过表达 Notch1 细胞内结构域则挽救了易位并增强了整合素β1 的激活。我们的数据提供了证据表明 ADAM17 通过调节整合素β1 激活和 Notch1 信号通路成为恶性特性的重要决定因素。抑制 ADAM17 可能为预防 HCC 转移提供可行的治疗潜力。
