ArticleJournal of biomedical science2022
PTEN regulates invasiveness in pancreatic neuroendocrine tumors through DUSP19-mediated VEGFR3 dephosphorylation.
Article in Journal of biomedical science, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 17 citations in OpenAlex.
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- Integrated multi-omics analysis identifies key biomarkers associated with post-translational modifications and RNA methylation in clear cell renal cell carcinoma.Discover oncology · 2025Article
- An Update on Novel Pharmacotherapies for the Treatment of Neuroendocrine Tumors.International journal of molecular sciences · 2025Review
- SIRT7 facilitates endometrial cancer progression by regulating PTEN stability in an estrogen-dependent manner.Nature communications · 2025Article
- The HRAS-binding C2 domain of PLCη2 suppresses tumor-like synoviocytes and experimental arthritis in rheumatoid arthritis.Experimental & molecular medicine · 2025Article
- Article
- An Overview of Altered Pathways Associated with Sensitivity to Platinum-Based Chemotherapy in Neuroendocrine Tumors: Strengths and Prospects.International journal of molecular sciences · 2024Review
- Pseudolaric Acid B Inhibits FLT4-induced Proliferation and Migration in Non-small Cell Lung Cancer.Anti-cancer agents in medicinal chemistry · 2024Article
- Endoscopic ultrasonography-based intratumoral and peritumoral machine learning radiomics analyses for distinguishing insulinomas from non-functional pancreatic neuroendocrine tumors.Frontiers in endocrinology · 2024Article
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- Extraction, Purification, Structural Characteristics, Health Benefits, and Application of the Polysaccharides fromMolecules (Basel, Switzerland) · 2023Review
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8 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundPhosphatase and tensin homolog (PTEN) is a tumor suppressor. Low PTEN expression has been observed in pancreatic neuroendocrine tumors (pNETs) and is associated with increased liver metastasis and poor survival. Vascular endothelial growth factor receptor 3 (VEGFR3) is a receptor tyrosine kinase and is usually activated by binding with vascular endothelial growth factor C (VEGFC). VEGFR3 has been demonstrated with lymphangiogenesis and cancer invasiveness. PTEN is also a phosphatase to dephosphorylate both lipid and protein substrates and VEGFR3 is hypothesized to be a substrate of PTEN. Dual-specificity phosphatase 19 (DUSP19) is an atypical DUSP and can interact with VEGFR3. In this study, we investigated the function of PTEN on regulation of pNET invasiveness and its association with VEGFR3 and DUSP19.
methodsPTEN was knocked down or overexpressed in pNET cells to evaluate its effect on invasiveness and its association with VEGFR3 phosphorylation. In vitro phosphatase assay was performed to identify the regulatory molecule on the regulation of VEGFR3 phosphorylation. In addition, immunoprecipitation, and immunofluorescence staining were performed to evaluate the molecule with direct interaction on VEGFR3 phosphorylation. The animal study was performed to validate the results of the in vitro study.
resultsThe invasion and migration capabilities of pNETs were enhanced by PTEN knockdown accompanied with increased VEGFR3 phosphorylation, ERK phosphorylation, and increased expression of epithelial-mesenchymal transition molecules in the cells. The enhanced invasion and migration abilities of pNET cells with PTEN knockdown were suppressed by addition of the VEGFR3 inhibitor MAZ51, but not by the VEGFR3-Fc chimeric protein to neutralize VEGFC. VEGFR3 phosphorylation is responsible for pNET cell invasiveness and is VEGFC-independent. However, an in vitro phosphatase assay failed to show VEGFR3 as a substrate of PTEN. In contrast, DUSP19 was transcriptionally upregulated by PTEN and was shown to dephosphorylate VEGFR3 via direct interaction with VEGFR3 by an in vitro phosphatase assay, immunoprecipitation, and immunofluorescence staining. Increased tumor invasion into peripheral tissues was validated in xenograft mouse model. Tumor invasion was suppressed by treatment with VEGFR3 or MEK inhibitors.
conclusionsPTEN regulates pNET invasiveness via DUSP19-mediated VEGFR3 dephosphorylation. VEGFR3 and DUSP19 are potential therapeutic targets for pNET treatment.
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