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GINS4 silencing mediates hepatocellular cancer cell proliferation, cycle and ferroptosis through POLE2
Jinni Yao1, Huaicheng Yang2, Meng Yuan1
1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Anhui University of Science and Technology, Huainan 232007, China; Graduate School of Anhui University of Science and Technology, Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital of Anhui University of Science and Technology, Huainan 232007, China.
Background:
GINS4 has been identified as a regulator associated with multiple types of cancers. However, the effects of GINS4 on hepatocellular carcinoma (HCC) have not been reported.
Methods:
GINS4 expression in HCC was evaluated utilizing UALCAN database. The relationship between the expression of GINS4 and the survival probability of HCC patients was analyzed using Kaplan-Meier Plotter. Cell viability was evaluated by CCK8 assay and EDU assay. qRT-PCR and western blot were performed to examine GINS4 expression. The level of cell cycle was measured by flow cytometry and western blot. Fe2+ level and ferroptosis-related proteins were measured by corresponding kits and western blot. Lipid peroxidation was explored by C11 BODIPY 581/591 probe. STRING database and HDOCK database were performed to predict the binding of GINS4 to POLE2. Immunofluorescence and western blotting was adopted for assessing cell autophagy and mTOR signaling pathway. Ki67 and GPX4 levels were measured by immunohistochemistry. The expression levels of POLE2/PI3K/AKT were assessed by western blot.
Results:
The data indicated that GINS4 expression was upregulated in HCC. Knockdown of GINS4 alleviated the proliferation and cycle and promoted ferroptosis of HuH7 cells. GINS4 was proved to bind to POLE2 and the silencing of GINS4 inhibited the expression of POLE2. GINS4 knockdown accelerated ferroptosis in HuH7 cells. POLE2 overexpression reversed the influences of GINS4 silencing on proliferation and cycle, and also ferroptosis. In addition, interference with GINS4 suppressed the activation of PI3K/AKT signaling via POLE2. In vivo experiments illustrated that GINS4 deletion suppressed HCC tumor growth, increased the GPX4 expression and restrained the Ki67 level, as well as reducing POLE2/PI3K/AKT signaling.
Conclusion:
GINS4 silencing suppressed proliferation and cycle while promoted ferroptosis in HCC cells by regulating PI3K/AKT signaling via binding to POLE2.
Insights
GINS4 promotes hepatocellular carcinoma (HCC) by increasing cell proliferation and inhibiting ferroptosis. Silencing GINS4 halts HCC growth by targeting the POLE2/PI3K/AKT pathway.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- GINS4 is implicated in various cancers.
- Its role in hepatocellular carcinoma (HCC) remains unexplored.
Purpose of the Study:
- To investigate the role and mechanism of GINS4 in HCC progression.
- To explore GINS4's impact on cell proliferation, cell cycle, and ferroptosis in HCC.
Main Methods:
- Analyzed GINS4 expression in HCC using UALCAN database.
- Assessed cell viability, proliferation, cell cycle, and ferroptosis markers.
- Investigated GINS4-POLE2 interaction and downstream signaling pathways (PI3K/AKT).
- Validated findings in vitro and in vivo models.
Main Results:
- GINS4 expression is upregulated in HCC.
- GINS4 knockdown inhibited HCC cell proliferation and cell cycle progression.
- GINS4 silencing promoted ferroptosis by upregulating GPX4 and downregulating lipid peroxidation.
- GINS4 binds to POLE2, inhibiting the PI3K/AKT pathway and suppressing tumor growth in vivo.
Conclusions:
- GINS4 promotes HCC progression by enhancing cell proliferation and suppressing ferroptosis.
- GINS4 exerts its effects by binding to POLE2 and regulating the PI3K/AKT signaling pathway.
- Targeting GINS4 presents a potential therapeutic strategy for HCC.
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