ArticleInternational journal of molecular sciences2020
Role of Nuclear Claudin-4 in Renal Cell Carcinoma.
Article in International journal of molecular sciences, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 20 citations in OpenAlex.
- Targeting claudins in cancer.Nature reviews. Drug discovery · 2026Review
- Repression of Connexin26 hemichannel activity protects the barrier function of respiratory airway epithelial cells against LPS-induced alteration.Cell communication and signaling : CCS · 2025Article
- Article
- Claudins: from gatekeepers of epithelial integrity to potential targets in hepato-pancreato-biliary cancers.Frontiers in oncology · 2024Review
- Claudin-4: A New Molecular Target for Epithelial Cancer Therapy.International journal of molecular sciences · 2023Review
- OCLN as a novel biomarker for prognosis and immune infiltrates in kidney renal clear cell carcinoma: an integrative computational and experimental characterization.Frontiers in immunology · 2023Article
- Tumorigenic effects of human mesenchymal stromal cells and fibroblasts on bladder cancer cells.Frontiers in oncology · 2023Article
- Protein Kinase C (PKC) Isozymes as Diagnostic and Prognostic Biomarkers and Therapeutic Targets for Cancer.Cancers · 2022Review
- TGF-β induces GBM mesenchymal transition through upregulation of CLDN4 and nuclear translocation to activate TNF-α/NF-κB signal pathway.Cell death & disease · 2022Article
- Loss of Claudin-4 Reduces DNA Damage Repair and Increases Sensitivity to PARP Inhibitors.Molecular cancer therapeutics · 2022Article
- Identification of a claudin-low subtype in clear cell renal cell carcinoma with implications for the evaluation of clinical outcomes and treatment efficacy.Frontiers in immunology · 2022Article
- The role and mechanism of claudins in cancer.Frontiers in oncology · 2022Review
- Dysregulated expression of claudins in cancer.Oncology letters · 2021Review
- Context-Dependent Roles of Claudins in Tumorigenesis.Frontiers in oncology · 2021Review
- Immunoexpression of Claudins -3, -4 and -7 in prostate adenocarcinomas.Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologieArticle
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Authors and funding
16 authors at 3 institutions in 2 countries.
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Abstract
Claudin-4 (CLDN4) is a tight junction protein to maintain the cancer microenvironment. We recently reported the role of the CLDN4 not forming tight junction in the induction of epithelial-mesenchymal transition (EMT). Herein, we investigated the role of CLDN4 in renal cell carcinoma (RCC), focusing on CLDN4. CLDN4 expression in 202 RCCs was examined by immunostaining. CLDN4 phosphorylation and subcellular localization were examined using high metastatic human RCC SN12L1 and low metastatic SN12C cell lines. In 202 RCC cases, the CLDN4 expression decreased in the cell membrane and had no correlation with clinicopathological factors. However, CLDN4 was localized in the nucleus in 5 cases (2%), all of which were pT3. Contrastingly, only 6 of 198 nuclear CLDN4-negative cases were pT3. CLDN4 was found in the nuclear fraction of a highly metastatic human RCC cell line, SN12L1, but not in the low metastatic SN12C cells. In SN12L1 cells, phosphorylation of tyrosine and serine residues was observed in cytoplasmic CLDN4, but not in membranous CLDN4. In contrast, phosphorylation of serine residues was observed in nuclear CLDN4. In SN12L1 cells, CLDN4 tyrosine phosphorylation by EphA2/Ephrin A1 resulted in the release of CLDN4 from tight junction and cytoplasmic translocation. Furthermore, protein kinase C (PKC)-ε phosphorylated the CLDN4 serine residue, resulting in nuclear import. Contrarily, in SN12C cells that showed decreased expression of EphA2/Ephrin A1 and PKCε, the activation of EphA2/EphrinA1 and PKCε induced cytoplasmic and nuclear translocation of CLDN4, respectively. Furthermore, the nuclear translocation of CLDN4 promoted the nuclear translocation of Yes-associated protein (YAP) bound to CLDN4, which induced the EMT phenotype. These findings suggest that the release of CLDN4 by impaired tight junction might be a mechanism underlying the malignant properties of RCC. These findings suggest that the release of CLDN4 by impaired tight junction might be one of the mechanisms of malignant properties of RCC.
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