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MicroRNAs as Potential Regulators of GSK-3β in Renal Cell Carcinoma.

ABSTRACT: The prognosis of patients with advanced renal cell carcinoma (RCC) has improved with newer therapies, including molecular-targeted therapies and immuno-oncology agents. Despite these therapeutic advances, many patients with metastatic disease remain uncured. Inhibition of glycogen synthase kinase-3β (GSK-3β) is a promising new therapeutic strategy for RCC; however, the precise regulatory mechanism has not yet been fully elucidated. MicroRNAs (miRNAs) act as post-translational regulators of target genes, and we investigated the potential regulation of miRNAs on GSK-3β in RCC. We selected nine candidate miRNAs from three databases that could potentially regulate GSK-3β. Among these, hsa-miR-4465 (miR-4465) was downregulated in RCC cell lines and renal cancer tissues. Furthermore, luciferase assays revealed that miR-4465 directly interacted with the 3' untranslated region of GSK-3β, and Western blot analysis showed that overexpression of miR-4465 significantly decreased GSK-3β protein expression. Functional assays showed that miR-4465 overexpression significantly suppressed cell invasion of A498 and Caki-1 cells; however, cell proliferation and migration were suppressed only in Caki-1 and A498 cells, respectively, with no effect on cell cycle and apoptosis. In conclusion, miR-4465 regulates GSK-3β expression but does not consistently affect RCC cell function as a single molecule. Further comprehensive investigation of regulatory networks is required in this field.

SUBMITTER: Murata M

PROVIDER: S-EPMC10529713 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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MicroRNAs as Potential Regulators of GSK-3β in Renal Cell Carcinoma.

Murata Masaki M Bilim Vladimir V Shirono Yuko Y Kazama Akira A Hiruma Kaede K Tasaki Masayuki M Tomita Yoshihiko Y

Current issues in molecular biology 20230911 9

The prognosis of patients with advanced renal cell carcinoma (RCC) has improved with newer therapies, including molecular-targeted therapies and immuno-oncology agents. Despite these therapeutic advances, many patients with metastatic disease remain uncured. Inhibition of glycogen synthase kinase-3β (GSK-3β) is a promising new therapeutic strategy for RCC; however, the precise regulatory mechanism has not yet been fully elucidated. MicroRNAs (miRNAs) act as post-translational regulators of targe ...[more]

PMID: 37754254

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Project description:BackgroundAbnormal expression of Fanconi anaemia complementation group I (FANCI) has been implicated in carcinogenesis. However, the precise role of FANCI in the development of hepatocellular carcinoma (HCC) remains unclear.Materials & methodsWe conducted a comprehensive bioinformatics analysis of FANCI's role based on HCC patient sequencing data in the TCGA and GEO databases. Then, we performed qPCR, Western blotting (WB), and immunohistochemistry (IHC) assays. SiRNA-mediated knockdown of FANCI was conducted, followed by CCK-8, EdU staining, and colony formation experiments to evaluate the impact of FANCI knockdown on HCC cell behaviour. Flow cytometry was employed to explore alterations in the cell cycle after FANCI knockdown in HCC cell lines. Furthermore, RNA sequencing was performed to investigate potential mechanisms following FANCI knockdown, and WB analysis was used to validate the corresponding pathway.ResultsOur bioinformatics analysis revealed elevated expression of FANCI in HCC, which was subsequently validated through qPCR, WB, and IHC assays. High expression of FANCI was significantly associated with a poor prognosis in HCC patients. Univariate and multivariate Cox regression analyses identified FANCI as an independent prognostic risk factor for HCC patients. Additionally, the coexpressed genes of FANCI were found to be associated with multiple cancer pathways. Knockdown of FANCI expression significantly inhibited HCC cell proliferation and colony formation by inducing cell cycle arrest. Further WB analysis revealed that FANCI knockdown suppressed the expression of Cyclin D1 and p-AKT while increasing the expression of GSK-3β in HCC cells. However, no significant differences were observed in the expression levels of AKT and PI3K.ConclusionOverall, our research provides substantial proof of FANCI's crucial function as an oncogene in HCC. It could serve as a potential prognostic marker, therapeutic target, and tumorigenic factor in HCC.

Dataset Information

MicroRNAs as Potential Regulators of GSK-3β in Renal Cell Carcinoma.

Publications

MicroRNAs as Potential Regulators of GSK-3β in Renal Cell Carcinoma.

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