LINC00346/β-catenin/MYC 轴的正反馈环促进肝细胞癌的发展。
A positive feedback loop involving the LINC00346/β-catenin/MYC axis promotes hepatocellular carcinoma development.
机构信息
Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi, China.
Department of Nuclear Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi, China.
出版信息
Cell Oncol (Dordr). 2020 Feb;43(1):137-153. doi: 10.1007/s13402-019-00478-4. Epub 2019 Nov 5.
PURPOSE
In 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.
METHODS
The 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.
RESULTS
We 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.
CONCLUSIONS
Our 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.
目的
近年来，长链非编码 RNA（lncRNA）作为癌症发展的重要调控因子受到越来越多的关注。然而，目前仍有很大一部分 lncRNA 尚未得到详细描述，LINC00346 在肝细胞癌（HCC）中的功能作用仍不清楚。
方法
通过体外和体内实验研究 LINC00346 在 HCC 发展中的作用。使用荧光素酶报告、RT-qPCR 和 Western blot 实验评估 LINC00346、miR-542-3p 和 WDR18 之间的相互作用。进行缺失和获得功能实验，以评估 LINC00346、miR-542-3p 和 WDR18 在 HCC 细胞活力、增殖、迁移和侵袭中的作用。
结果
我们发现 LINC00346 在原发性 HCC 组织和 HCC 衍生细胞系中上调，并且 LINC00346 可能促进 HCC 细胞活力、增殖、迁移和侵袭。此外，我们发现 LINC00346 可能通过竞争性结合 miR-542-3p 来调节 WDR18 的表达。在原发性 HCC 组织中发现该 miRNA 下调，作为一种肿瘤抑制因子，可以抑制 HCC 细胞活力、增殖、迁移和侵袭。相反，在原发性 HCC 组织中发现 WDR18 上调，作为一种癌基因。进一步的功能研究表明，WDR18 可以在 HCC 细胞中激活 Wnt/β-catenin 信号通路及其下游效应物。我们还发现，LINC00346 通过竞争性吸附 miR-542-3p，可以增强 HCC 细胞中 WDR18 的表达并激活 Wnt/β-catenin 信号通路。最后，在 HCC 细胞中发现了涉及 LINC00346、β-catenin 和 MYC 的正反馈环。
结论
我们的研究结果表明，LINC00346 在 HCC 细胞中通过涉及 LINC00346、β-catenin 和 MYC 的正反馈环发挥致癌作用，这可能为设计新型 HCC 生物标志物和/或治疗策略提供依据。
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