Abstract
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 MACROD2 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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and its incidence and mortality rate are increasing[1,2,3]
We identified a new tumor suppressor gene, MACROD2, which was the gene most frequently affected by structural variations (SVs) in HCC
We validated those findings in samples of tumor tissues from patients with HCC and found that low MACROD2 expression was predictive of poor patient outcomes
Summary
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and its incidence and mortality rate are increasing[1,2,3]. High rates of recurrence and metastasis limit the long-term survival of patients with HCC despite advances in surgical treatments and patient management that have led to some improvements in patient outcomes[6,7,8]. It is critical to gain an understanding of the molecular mechanisms underlying HCC growth and metastasis so that new treatments can be developed to improve long-term survival rates among patients with HCC. Mutations in the coding regions of TP53 and CTNNB1 affect 25–30% of patients with HCC and, along with low-frequency mutations in some other genes (e.g., AXIN1, ARID2, ARID1A, TSC1/TSC2), define core pathways that are commonly de-regulated in HCC. It is largely unknown what roles genes affected by structural variations (SVs) play in HCC
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