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. 2025 Apr 17;16(1):548.
doi: 10.1007/s12672-025-02328-2.

Unraveling the oncogenic role of LINC00504 and its interaction with miR-545-3p and ARIHI in hepatocellular carcinoma: novel insights for molecular therapy

E Ke #  1 , Kai Yang #  1 , Qin Zhang  1 , Cheng Luo  1 , Zhiyong Hu  1 , Jing Wang  2 , Hai Zhang  3
Affiliations

Unraveling the oncogenic role of LINC00504 and its interaction with miR-545-3p and ARIHI in hepatocellular carcinoma: novel insights for molecular therapy

E Ke et al. Discov Oncol. .

Abstract

Objectives: Hepatocellular carcinoma (HCC) is a serious global health threat associated with high morbidity and mortality. The importance of long non-coding RNAs (lncRNAs) in tumor progression is growing. The aim of this study was to explore the expression, functional properties and molecular mechanisms of LINC00504 in HCC.

Materials and methods: Tumor tissue samples from HCC patients were collected to analyze the expression of LINC00504, miR-545-3p, and ARIH1 mRNA using RT-qPCR, and compared with various HCC cell lines (PLC/PRF/5, SNU-182, Hep3B, HuH-7) and a human normal liver epithelial cell line (THLE-2). Cell proliferation, apoptosis, and invasion were assessed using transfection vectors, CCK8 assay, flow cytometry, and Transwell. Interactions among LINC00504, miR-545-3p, and ARIH1 were confirmed through database predictions and luciferase reporter gene assays.

Results: LINC00504 was underexpressed in HCC tissues and cell lines. Upregulation of LINC00504 inhibited cell proliferation, induced apoptosis, increased Bax and Caspase-3, decreased Bcl-2 mRNA, and suppressed invasion. miR-545-3p was overexpressed in HCC cells and was negatively regulated by LINC00504. Overexpression of miR-545-3p counteracted the effects of LINC00504 upregulation. ARIH1 was underexpressed in HCC tissues and had a negative correlation with miR-545-3p. miR-545-3p negatively regulated ARIH1 expression, and ARIH1 overexpression overturned the promotional effects of miR-545-3p on HCC cells.

Conclusion: This study uncovers the significant tumor-suppressing role of LINC00504 in HCC, potentially through a mechanism involving the targeting of miR-545-3p, which in turn inhibits the ARIH1. These findings offer new potential targets for HCC molecular treatment.

Keywords: ARIH1; Cellular processes; HCC; LINC00504; MiR-545-3p.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was performed in line with the principles of the Declaration of Helsinki. All protocols of this investigation were approved by the Ethics Committee of Huangshi Central Hospital. The participants'right to be informed about the study was ensured and written informed consent was obtained from all individual participants included in the study. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
A LINC00504 downregulation noted in HCC via LncBook. B LINC00504 expression reduced in HCC tissues. C LINC00504 significantly downregulated in HCC cell lines compared to THLE-2. *** P < 0.001, vs. Normal or THLE-2
Fig. 2
Fig. 2
A SNU-182 and HuH-7 cell lines were transfected with the oe-LINC00504 plasmid to induce LINC00504 upregulation. B, C LINC00504 upregulation inhibits cell proliferation in SNU-182 and HuH-7 cells. D LINC00504 upregulation induces apoptosis in cancer cells. E, F LINC00504 upregulation promotes Bax/Caspase-3 and inhibits Bcl-2 in SNU-182 and HuH-7. G LINC00504 upregulation inhibits cancer cell invasion. *** P < 0.001, vs. CK
Fig. 3
Fig. 3
A GEDS database shows miR-545-3p upregulation in hepatocellular carcinoma (LIHC) tissues. B miR-545-3p upregulated in HCC tissues. C miR-545-3p negatively correlates with LINC00504 in HCC. D In HCC cell lines in comparison to THLE-2, miR-545-3p upregulated. ***P < 0.001, vs. Normal or THLE-2
Fig. 4
Fig. 4
A The binding sites between miR-545-3p and LINC00504, with primer sequences shown for WT and MT. B, C miR-545-3p negatively affects luciferase activity of WT-LINC00504 in SNU-182 and HuH-7 cells, not MT. D miR-545-3p overexpression does not alter LINC00504 expression in HCC cell lines. E LINC00504 overexpression significantly inhibits miR-545-3p expression in HCC cell lines. *** P < 0.001, vs. CK; ## P < 0.001, vs. oe- LINC00504
Fig. 5
Fig. 5
A, B miR-545-3p overexpression counters LINC00504-mediated inhibition of SNU-182 and HuH-7 cell proliferation. C miR-545-3p reverses LINC00504-induced apoptosis. D, E miR-545-3p alters LINC00504 effects on Bax, Caspase-3, Bcl-2. F miR-545-3p reverses the inhibition of LINC00504 on cancer cell invasion. *** P < 0.001, vs. CK; ## P < 0.001, vs. oe- LINC00504
Fig. 6
Fig. 6
A Binding sites between ARIH1 and miR-545-3p identified. B, C miR-545-3p reduces luciferase activity of WT-ARIH1. D miR-545-3p levels are unaffected by ARIH1 overexpression. E miR-545-3p inhibits ARIH1 expression. *** P < 0.001, vs. miR-NC; ## P < 0.001, vs. miR-mimic
Fig. 7
Fig. 7
A, B ARIH1 reverses miR-545-3p promotion of SNU-182, and HuH-7 cell proliferation. C ARIH1 reverses the inhibition of apoptosis by miR-545-3p. D, E ARIH1 alters miR-545-3p effects on Bax, Caspase-3, Bcl-2 in SNU-182 and HuH-7. F ARIH1 reverses miR-545-3p promotion of cancer cell invasion. *** P < 0.001, vs. miR-NC; ## P < 0.001, vs. miR-mimic
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