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GATA5 inhibits hepatocellular carcinoma cells malignant behaviours by blocking expression of reprogramming genes
Haipeng Feng1,2, Mingyue Zhu1,2, Ruizhu Zhang1,2
1Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Hainan Province, Haikou, PR. China.
Abstract:
Evidence indicated that GATA5 may suppress hepatocellular carcinoma (HCC) cell malignant transformation, but the mechanism of how GATA5 affects cancer cell reprogramming to inhibit HCC malignant behaviour is still unclear. In this study, we report that the expression of β-catenin and reprogramming genes p-Oct4, Nanog, Klf4, c-myc and EpCAM was significantly higher in HCC tissues compared to normal liver tissues. In contrast, the expression of GATA5 was significantly lower in HCC tissues compared to normal liver tissues. Transfection of CDH-GATA5 vectors into HCC cells (HLE, Bel 7402 and PLC/PRF/5 cells) increased the GATA5 expression and decreased the expression of β-catenin and reprogramming genes p-Oct4, Nanog, Klf4, c-myc and EpCAM. Increased GATA5 expression by transfection with its expression vectors was also able to inhibit the cell growth, colony formation and capability of migration, invasion, while promoting apoptosis in HCC cells. Results revealed that GATA5 co-localization with β-catenin in the cytoplasm, preventing β-catenin from entering the nucleus. Treatment with the specific Wnt/β-catenin pathway inhibitor salinomycin was able to reduce the expression of β-catenin and reprogramming genes. Salinomycin exerted a similar influence as GATA5, and siRNA-GATA5 restored β-catenin and reprogramming gene expression. This study demonstrates that an increase in the expression of GATA5 inhibits the expression of β-catenin and reprogramming genes and suppresses tumour growth, colony formation, metastasis and invasion, while promoting apoptosis in HCC cells. The mechanism of GATA5 inhibiting the malignant behaviours of HCC cells may involve in the disruption of the Wnt/β-catenin pathway and the reduction of reprogramming gene expression.
Insights
GATA5 suppresses hepatocellular carcinoma (HCC) by reducing β-catenin and reprogramming genes. This finding offers new insights into inhibiting HCC progression and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Hepatocellular carcinoma (HCC) progression is linked to elevated expression of β-catenin and reprogramming genes.
- The precise mechanism by which GATA5 suppresses HCC malignant transformation remains largely unknown.
Purpose of the Study:
- To elucidate the mechanism underlying GATA5's role in inhibiting HCC cell reprogramming and malignant behavior.
- To investigate the relationship between GATA5, β-catenin, and key reprogramming factors in HCC.
Main Methods:
- Quantitative analysis of GATA5, β-catenin, and reprogramming gene expression in HCC tissues versus normal liver tissues.
- Gene transfection to overexpress GATA5 in HCC cell lines (HLE, Bel 7402, PLC/PRF/5).
- Assessment of cell proliferation, colony formation, migration, invasion, and apoptosis following GATA5 modulation. Examination of GATA5 and β-catenin subcellular localization. Use of Wnt/β-catenin pathway inhibitor (salinomycin) and siRNA-GATA5 for mechanistic studies.
Main Results:
- GATA5 expression was significantly lower, while β-catenin and reprogramming genes (p-Oct4, Nanog, Klf4, c-myc, EpCAM) were higher in HCC tissues.
- Overexpression of GATA5 in HCC cells reduced β-catenin and reprogramming gene expression, inhibited cell growth, colony formation, migration, and invasion, and promoted apoptosis.
- GATA5 co-localized with β-catenin in the cytoplasm, impeding nuclear translocation. Inhibition of the Wnt/β-catenin pathway mimicked GATA5's effects, and GATA5 knockdown reversed these changes.
Conclusions:
- GATA5 functions as a tumor suppressor in HCC by downregulating β-catenin and reprogramming gene expression.
- GATA5 inhibits HCC cell malignant behaviors, including proliferation, metastasis, and invasion, potentially through disruption of the Wnt/β-catenin pathway.
- These findings highlight GATA5 as a potential therapeutic target for hepatocellular carcinoma treatment.
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