Zhou Zheng-Jun, Luo Chu-Bin, Xin Hao-Yang, Hu Zhi-Qiang, Zhu Gui-Qi, Li Jia, Zhou Shao-Lai
1Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032 Shanghai, China.
2Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, 200032 Shanghai, China.
NPJ Genom Med. 2020 Apr 1;5:15. doi: 10.1038/s41525-020-0122-7. eCollection 2020.
Structural variations (SVs) influence the development and progression of multiple types of cancer. The genes affected by SVs in hepatocellular carcinoma (HCC) and their contribution to tumor growth and metastasis remain unknown. In this study, through whole-genome sequencing (WGS), we identified as the gene most frequently affected by SVs, which were associated with low MACROD2 expression levels. Low MACROD2 expression was predictive of tumor recurrence and poor overall survival. MACROD2 expression was decreased in HCC cell lines, especially those with high metastatic potential. MACROD2 knockdown in HCC cells markedly enhanced proliferation and invasiveness in vitro and tumor progression in vivo and promoted epithelial-mesenchymal transition (EMT). By contrast, MACROD2 overexpression reversed EMT and inhibited HCC growth and metastasis. Mechanistically, MACROD2 deficiency suppressed glycogen synthase kinase-3β (GSK-3β) activity and activated β-catenin signaling, which mediated the effect of MACROD2 on HCC. In clinical HCC samples, decreased MACROD2 expression was correlated with the activation of GSK-3β/β-catenin signaling and the EMT phenotype. Overall, our results revealed that MACROD2 is frequently affected by SVs in HCC, and its deficiency promotes tumor growth and metastasis by activating GSK-3β/β-catenin signaling.
结构变异（SVs）影响多种类型癌症的发生和发展。肝细胞癌（HCC）中受SVs影响的基因及其对肿瘤生长和转移的作用尚不清楚。在本研究中，通过全基因组测序（WGS），我们确定 为受SVs影响最频繁的基因，其与低水平的MACROD2表达相关。低水平的MACROD2表达可预测肿瘤复发和总体生存率较差。在HCC细胞系中，尤其是具有高转移潜能的细胞系中，MACROD2表达降低。在HCC细胞中敲低MACROD2可显著增强体外增殖和侵袭能力以及体内肿瘤进展，并促进上皮-间质转化（EMT）。相反，MACROD2过表达可逆转EMT并抑制HCC生长和转移。机制上，MACROD2缺陷抑制糖原合酶激酶-3β（GSK-3β）活性并激活β-连环蛋白信号通路，该信号通路介导了MACROD2对HCC的作用。在临床HCC样本中，MACROD2表达降低与GSK-3β/β-连环蛋白信号通路的激活和EMT表型相关。总体而言，我们的结果表明，MACROD2在HCC中经常受SVs影响，其缺陷通过激活GSK-3β/β-连环蛋白信号通路促进肿瘤生长和转移。
