Protein phosphatase 2A-B55δ enhances chemotherapy sensitivity of human hepatocellular carcinoma under the regulation of microRNA-133b
Open accessAbstract
BACKGROUND: Hepatocellular carcinoma (HCC) remains a major public health problem worldwide. The identification of effective chemotherapeutic targets for advanced HCC patients is urgently required. In this study, we investigated the role of protein phosphatase 2A-B55δ subunit (PP2A-B55δ, encoded by the PPP2R2D gene) and related mechanisms affecting chemotherapy sensitivity of HCC. METHODS: Experimental approaches for measuring the levels of PPP2R2D mRNA and B55δ protein in HCC included bioinformatics analyses, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting (WB), immunofluorescence and immunohistochemistry assays. Cell cycle, migration, colony formation, apoptosis, and cell proliferation assays in stable PPP2R2D-knockdown and -overexpression cell lines in vitro, and tumorigenicity assays in vivo, were performed to explore the function of B55δ in cisplatin (cDDP) chemotherapy of HCC. Bioinformatics prediction, luciferase reporter assays, qRT-PCR, WB, and cell cycle analyses were used to reveal the regulatory relationship between microRNA-133b (miR-133b) and PPP2R2D expression. miR-133b mimic and inhibitor were used to elucidate the regulatory mechanism. RESULTS: Our studies showed that PPP2R2D expression was down-regulated in both HCC tumors and HCC cell lines. Treatment with cDDP increased the amount of B55δ protein. Artificially increasing the expression of B55δ counteracted cyclin-dependent kinase 1 activation, modulated transitions of the cell cycle, and increased the suppressive effect of cDDP on cell migration, colony formation, apoptosis, and proliferation in vitro and tumor growth in vivo, thus enhancing therapeutic efficiency. In contrast, knockdown of B55δ partially inhibited the effect of cDDP chemotherapy. miR-133b was shown to regulate PPP2R2D expression by binding to the 3'-untranslated region of PPP2R2D mRNA. The miR-133b/PPP2R2D signaling pathway affects the effectiveness of cDDP chemotherapy. CONCLUSIONS: PP2A-B55δ, regulated by miR-133b, enhances the sensitivity of HCC to cDDP chemotherapy. Our data indicate that PP2A-B55δ might be a novel and attractive target for increasing chemotherapy sensitivity of HCC.
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PPP2R2D is downregulated in hepatocellular carcinoma tumors and cell lines, possibly through miR133b upregulation.
“The B55δ-encoding gene PPP2R2D is downregulated in hepatocellular carcinoma (HCC) tumors and cell lines, by a mechanism that may involve upregulation of miR133b.”
From PP2A holoenzymes, substrate specificity driving cellular functions and deregulation in cancer (2019) · cites this paper as Zhuang et al., 2016
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- Authors
- Zhuang, Q., Zhou, T., He, C., Zhang, S., Qiu, Y., Luo, B., Zhao, R., Liu, H., Lin, Y., & Lin, Z.
- Affiliations
- Xiamen University (CN)
- Venue
- Journal of Experimental & Clinical Cancer Research
- Published
- 2016-04-14
- Volume
- 35
- Issue
- 1
- Pages
- 67-67
- ISSN
- 0392-9078 (ISSN-L)
- 1756-9966
- PMC
- PMC4831140
- OpenAlex
- W2336186020
- Cited by
- 38
- References
- 44
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 5
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81172705, 81402648)
- Early-stage Project of National Key Basic Research Program of China (2014CB560710)
- National Natural Science Foundation of China Key Program (81130052)
- Education Scientific Research Project of Young Teachers in Fujian Province (JA14004)
- Project funded by Science Foundation of Xiamen City (3502Z20140045)
- the Project funded by Science Foundation of Fujian Province (2014Y2004)
- Shanhai Funding of Xiamen University (2013SH007)
- the Natural Science Foundation of Fujian Province of China (2014J01372)
- Natural Science Foundation of Fujian Province of China (2015J01344)
- Xiamen Municipal Bureau of Ocean and Fisheries (14PYY051SF04)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- hepatocellular carcinoma, microRNA-133b, cisplatin, chemosensitivity, cyclin-dependent kinase 1, cell cycle regulation, apoptosis, cell migration, tumor growth, 3' untranslated region, chemoresistance, microRNA target regulation, drug target identification, liver cancer
- MeSH terms
- Animals, Antineoplastic Agents, Cell Cycle, Cell Movement, Cisplatin, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Gene Expression Regulation, Neoplastic, Xenograft Model Antitumor Assays, MicroRNAs, Cell Line, Tumor, Mice, Protein Phosphatase 2, Hep G2 Cells
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