Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
J Cell Mol Med. 2021 Jan;25(2):1024-1034. doi: 10.1111/jcmm.16167. Epub 2020 Dec 4.
Tetraspanin CD63 has been widely implicated in tumour progression of human malignancies. However, its role in the tumorigenesis and metastasis of hepatocellular carcinoma (HCC) remains unclear yet. In the present study, we aimed to investigate the specific function and underlying mechanisms of CD63 in HCC progression. CD63 expression in HCC tissues was detected using immunohistochemistry and quantitative real-time PCR analyses; effects of CD63 on HCC cell proliferation and migration were investigated by CCK-8 assay, colony formation assay, transwell assay and a xenograft model of nude mice. RNA-sequencing, bioinformatics analysis, dual-luciferase reporter assay and Western blot analysis were performed to explore the underlying molecular mechanisms. Results of our experiments showed that CD63 expression was frequently reduced in HCC tissues compared with adjacent normal tissues, and decreased CD63 expression was significantly associated with larger tumour size, distant site metastasis and higher tumour stages of HCC. Overexpression of CD63 inhibited HCC cell proliferation and migration, whereas knockdown of CD63 promoted these phenotypes. IL-6, IL-27 and STAT3 activity was regulated by CD63, and blockade of STAT3 activation impaired the promotive effects of CD63 knockdown on HCC cell growth and migration. Our findings identified a novel CD63-IL-6/IL-27-STAT3 axis in the development of HCC and provided a potential target for the diagnosis and treatment of this disease.
四跨膜蛋白 CD63 广泛参与人类恶性肿瘤的肿瘤进展。然而，其在肝细胞癌（HCC）发生和转移中的作用尚不清楚。在本研究中，我们旨在研究 CD63 在 HCC 进展中的特定功能和潜在机制。使用免疫组织化学和定量实时 PCR 分析检测 HCC 组织中的 CD63 表达；通过 CCK-8 测定、集落形成测定、Transwell 测定和裸鼠异种移植模型研究 CD63 对 HCC 细胞增殖和迁移的影响。进行 RNA 测序、生物信息学分析、双荧光素酶报告基因测定和 Western blot 分析以探索潜在的分子机制。我们的实验结果表明，与相邻正常组织相比，CD63 在 HCC 组织中经常表达降低，并且 CD63 表达降低与 HCC 肿瘤较大、远处转移和较高肿瘤分期显著相关。CD63 的过表达抑制 HCC 细胞的增殖和迁移，而 CD63 的敲低则促进这些表型。CD63 调节 IL-6、IL-27 和 STAT3 的活性，阻断 STAT3 激活可削弱 CD63 敲低对 HCC 细胞生长和迁移的促进作用。我们的研究结果确定了 HCC 发生发展中的一个新的 CD63-IL-6/IL-27-STAT3 轴，并为该疾病的诊断和治疗提供了一个潜在的靶点。
