A positive feedback loop involving the LINC00346/β-catenin/MYC axis promotes hepatocellular carcinoma development
A positive feedback loop involving the LINC00346/β-catenin/MYC axis promotes hepatocellular carcinoma development
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涉及 LINC00346/β-连环蛋白/MYC 轴的正反馈环促进肝细胞癌的发展
DOI：
10.1007/s13402-019-00478-4
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发表时间：
2019-11-05
影响因子：
6.6
通讯作者：
Chen, Xin
中科院分区：
文献类型：
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作者：
Zhang, Nuobei;Chen, Xin
目的近年来，长非编码RNA(Long Non Coding RNAs，LncRNAs)作为肿瘤发生发展的重要调控因子受到越来越多的关注。然而，到目前为止，大部分LINC00346在肝细胞癌中的功能还不清楚。方法通过体外和体内实验研究LINC00346在肝癌发生发展中的作用。LINC00346、miR-542-3p和WDR18之间的相互作用通过荧光素酶报告、RT-qPCR和Western blotting检测。LINC00346、miR-542-3p和WDR18在肝癌细胞存活、增殖、迁移和侵袭中的作用。结果发现LINC00346在原代肝癌组织和肝癌细胞系中表达上调，LINC00346可能促进肝癌细胞的存活、增殖、迁移和侵袭。此外，我们还发现LINC00346可能通过与miR-542-3p竞争性结合来调节WDR18的表达。这种miRNA被发现在原发肝癌组织中表达下调，并作为一种肿瘤抑制因子，可以抑制肝癌细胞的存活、增殖、迁移和侵袭。相比之下，WDR18在原发性肝癌组织中上调，并作为癌基因发挥作用。进一步的功能研究表明，WDR18可以激活肝癌细胞中的Wnt/β-catenin信号通路及其下游效应因子。我们还发现，LINC00346通过竞争性海绵切割miR-542-3p，可以增强WDR18在肝癌细胞中的表达，激活Wnt/β-catenin信号通路。结论LINC00346通过LINC00346、β-catenin和myc的正反馈环在肝癌细胞中发挥致癌作用，可能为设计新的肝癌生物标志物和/或治疗策略提供依据。
PurposeIn recent years, long noncoding RNAs (lncRNAs) have received increasing attention as important regulators of cancer development. As yet, however, a large fraction of them has not been characterized in detail, and the functional role of LINC00346 in hepatocellular carcinoma (HCC) has remained unclear.MethodsThe role of LINC00346 in HCC development was investigated using both in vitro and in vivo assays. Interactions between LINC00346, miR-542-3p and WDR18 were assessed using luciferase reporter, RT-qPCR and Western blotting assays. Loss- and gain-of-function experiments were performed to assess the roles of LINC00346, miR-542-3p and WDR18 in HCC cell viability, proliferation, migration and invasion.ResultsWe found that LINC00346 was upregulated in primary HCC tissues and HCC-derived cell lines and that LINC00346 may promote HCC cell viability, proliferation, migration and invasion. Furthermore, we found that LINC00346 may regulate WDR18 expression via competitively binding to miR-542-3p. This miRNA was found to be downregulated in primary HCC tissues and to act as a tumor suppressor that can inhibit HCC cell viability, proliferation, migration and invasion. In contrast, WDR18 was found to be upregulated in primary HCC tissues and to act as an oncogene. Additional functional studies indicated that WDR18 can activate the Wnt/β-catenin signaling pathway and its downstream effectors in HCC cells. We also found that LINC00346, through competitive sponging of miR-542-3p, may enhance the expression of WDR18 and activate the Wnt/β-catenin signaling pathway in HCC cells. Finally, a positive feedback loop involving LINC00346, β-catenin and MYC in HCC cells was uncovered.ConclusionsOur results indicate an oncogenic role of LINC00346 in HCC cells via a positive feedback loop involving LINC00346, β-catenin and MYC, and they may be instrumental for the design of novel HCC biomarkers and/or therapeutic strategies.