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A positive feedback loop involving the LINC00346/β-catenin/MYC axis promotes hepatocellular carcinoma development

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Abstract

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.

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Abbreviations

MTT:

1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan

HCC:

Hepatocellular carcinoma

lncRNA:

long non-coding RNA

FBS:

Fetal bovine serum

RT-qPCR:

Real-time quantitative PCR

DMEM:

Dulbecco’s Modified Eagle Medium

RPMI:

Roswell Park Memorial Institute

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Acknowledgments

We thank the Second Affiliated Hospital of Nanchang University for providing the 90 paired HCC and adjacent normal liver tissues. This work was supported by the National Natural Science Foundation of China (No.81760427).

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  1. Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi, China

    Nuobei Zhang

  2. Department of Nuclear Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330000, Jiangxi, China

    Xin Chen

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Zhang, N., Chen, X. A positive feedback loop involving the LINC00346/β-catenin/MYC axis promotes hepatocellular carcinoma development. Cell Oncol. 43, 137–153 (2020). https://doi.org/10.1007/s13402-019-00478-4

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