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.

中文翻译：

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涉及LINC00346 /β-catenin/ MYC轴的正反馈回路可促进肝细胞癌的发展。

目的

近年来，长的非编码RNA（lncRNA）作为癌症发展的重要调节剂受到越来越多的关注。然而，到目前为止，还没有详细描述其中的大部分，LINC00346在肝细胞癌（HCC）中的功能作用仍不清楚。

方法

使用体外和体内试验研究了LINC00346在HCC发生中的作用。LINC00346，miR-542-3p和WDR18之间的相互作用使用荧光素酶报告基因，RT-qPCR和Western印迹分析进行了评估。进行了功能丧失和功能获得实验，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衍生的细胞系中上调，并且LINC00346可能促进HCC细胞的活力，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。发现该miRNA在原发性HCC组织中被下调，并充当可抑制HCC细胞活力，增殖，迁移和侵袭的肿瘤抑制因子。相反，发现WDR18在原发性肝癌组织中被上调并起癌基因的作用。其他功能研究表明，WDR18可以激活HCC细胞中的Wnt /β-catenin信号传导途径及其下游效应物。我们还发现LINC00346通过miR-542-3p的竞争性海绵化，可能增强WDR18的表达并激活HCC细胞中的Wnt /β-catenin信号通路。最后，在肝癌细胞中发现了涉及LINC00346，β-catenin和MYC的正反馈回路。

结论

我们的结果表明，LINC00346通过涉及LINC00346，β-catenin和MYC的正反馈回路在HCC细胞中具有致癌作用，并且它们可能对设计新型HCC生物标记物和/或治疗策略具有帮助。