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Role of Nuclear Claudin-4 in Renal Cell Carcinoma

Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, Jiangsu, China
Drug Innovation Center, Graduate School of Pharmaceutical Sciences, Osaka University, 6-1 Yamadaoka, Suita, Osaka 565-0871, Japan
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(21), 8340;
Received: 20 August 2020 / Revised: 28 October 2020 / Accepted: 4 November 2020 / Published: 6 November 2020
(This article belongs to the Special Issue Molecular Research on Urology 2.0)
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. View Full-Text
Keywords: CLDN4; PKCε; EphA2; Ephrin A1; EMT CLDN4; PKCε; EphA2; Ephrin A1; EMT
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MDPI and ACS Style

Owari, T.; Sasaki, T.; Fujii, K.; Fujiwara-Tani, R.; Kishi, S.; Mori, S.; Mori, T.; Goto, K.; Kawahara, I.; Nakai, Y.; Miyake, M.; Luo, Y.; Tanaka, N.; Kondoh, M.; Fujimoto, K.; Kuniyasu, H. Role of Nuclear Claudin-4 in Renal Cell Carcinoma. Int. J. Mol. Sci. 2020, 21, 8340.

AMA Style

Owari T, Sasaki T, Fujii K, Fujiwara-Tani R, Kishi S, Mori S, Mori T, Goto K, Kawahara I, Nakai Y, Miyake M, Luo Y, Tanaka N, Kondoh M, Fujimoto K, Kuniyasu H. Role of Nuclear Claudin-4 in Renal Cell Carcinoma. International Journal of Molecular Sciences. 2020; 21(21):8340.

Chicago/Turabian Style

Owari, Takuya; Sasaki, Takamitsu; Fujii, Kiyomu; Fujiwara-Tani, Rina; Kishi, Shingo; Mori, Shiori; Mori, Takuya; Goto, Kei; Kawahara, Isao; Nakai, Yasushi; Miyake, Makito; Luo, Yi; Tanaka, Nobumichi; Kondoh, Masuo; Fujimoto, Kiyohide; Kuniyasu, Hiroki. 2020. "Role of Nuclear Claudin-4 in Renal Cell Carcinoma" Int. J. Mol. Sci. 21, no. 21: 8340.

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