A Positive Feedback Loop Involving the LINC00346/β-Catenin/MYC Axis Promotes Hepatocellular Carcinoma Progression

Background: Long non-coding RNAs (lncRNAs) have received increased attention to act as important regulators in cancer progression. However, a large fraction of them have not been characterized and the functional mechanism of LINC00346 in hepatocellular carcinoma (HCC) remains unclear. Methods: The role of LINC00346 in HCC was investigated in vitro and in vivo. The interaction between LINC00346, miR-542-3p, and WDR18 was identified using luciferase activity assays, RT-qPCR, and western blotting. Loss (or gain)-of-function experiments were performed to investigate the biological roles of LINC00346, miR-542-3p, and WDR18 on cell viability, proliferation, migration, invasion, and cell apoptosis. Findings: We demonstrated that LINC00346 was upregulated in HCC, and LINC00346 can promote cell viability, proliferation, migration and invasion, but repress apoptosis of HCC cells. Furthermore, we revealed that LINC00346 regulates WDR18 expression via competitive binding with miR-542-3p, which was downregulated in HCC and acted as a tumor suppressor that can inhibite cell viability, proliferation, migration and invasion, but promote apoptosis of HCC cells, whereas WDR18 was upregulated in HCC and functioned as an oncogenic role in HCC. Moreover, further functional mechanism investigation illustrated that WDR18 activates the Wnt/β-catenin signaling pathway and downstream moleculars. Additionally, we found that LINC00346 acts as ceRNA via competitively sponging miR-542-3p, enhancing the expression of WDR18 and activating the Wnt/β-catenin signaling pathway in HCC. Finally, a positive feedback loop involving LINC00346, β-catenin, and MYC in HCC cells was demonstrated. Interpretation: Our results uncover a potential mechanism to understand the oncogenic role of LINC00346 via a positive feedback loop involving LINC00346, β-catenin, and MYC in HCC cells, which provides profoundly a prospective biomarker and potential therapeutic target in HCC. Funding Statement: This work was supported by the National Natural Science Foundation of China (No.81760427). Declaration of Interests: The authors declare that they have no competing financial interests. Ethics Approval Statement: The process was approved by Ethics Committee of The Second Affiliated Hospital of Nanchang University, and all patients were informed and written informed consent. Animal protocols were approved by The Second Affiliated Hospital of Nanchang University Animal Care and Use Committee.