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Possibility of Targeting Claudin-2 in Therapy for Human Endometrioid Endometrial Carcinoma

  • Gynecologic Oncology: Original Article
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Abstract

Claudin-2 (CLDN-2) is a leaky-type tight junction protein, and its overexpression increases tumorigenesis of some types of cancer cells. In the present study, to examine the possibility of targeting CLDN-2 in the therapy for endometrioid endometrial adenocarcinoma, we investigated the regulation and role of CLDN-2 in endometriosis and endometrioid endometrial adenocarcinoma. In endometrioid endometrial adenocarcinoma tissues, marked upregulation of CLDN-2 was observed together with malignancy, while in endometriosis tissues, a change in the localization of CLDN-2 was observed. In cells of the endometrial adenocarcinoma cell line Sawano, which highly express CLDN-2, downregulation of CLDN-2 induced by the siRNA upregulated the epithelial barrier and inhibited cell migration. Furthermore, the downregulation of CLDN-2 affected the cell cycle and inhibited cell proliferation. In Sawano cells cultured with high-glucose medium, CLDN-2 expression was downregulated at the mRNA and protein levels. The high-glucose medium upregulated the epithelial barrier, cell proliferation, and migration, and inhibited cell invasion. The histone deacetylase (HDAC) inhibitor tricostatin A (TSA), which has antitumor effects, downregulated CLDN-2 expression, cell proliferation, invasion, and migration, and upregulated the epithelial barrier. The mitochondrial respiration level, an indicator of cancer metabolism, was downregulated by CLDN-2 knockdown and upregulated by the high-glucose condition. Taken together, these results indicated that overexpression of CLDN-2 closely contributed to the malignancy of endometrioid endometrial adenocarcinoma. Downregulation of CLDN-2 via the changes of the glucose concentration and treatment with HDAC inhibitors may be important in the therapy for endometrial cancer.

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Acknowledgments

This work was supported by the Ministry of Education, Culture, Sports, Science, and Technology, and the Ministry of Health, Labour and Welfare of Japan.

Authors’ Contributions Statement

T. Okada, T. Konno and T. Kojima designed and coordinated the study and wrote the main manuscript text. T. Okada, T. Konno and T. Kojima analyzed the data. T. Kohno, H.S., S.S. and T.S. contributed reagents/materials. All authors reviewed the manuscript.

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Authors and Affiliations

  1. Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, 060-8556, Japan

    Tadahi Okada, Takumi Konno, Takayuki Kohno, Kimihito Saito & Takashi Kojima

  2. Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan

    Tadahi Okada, Hiroshi Shimada, Kimihito Saito, Seiro Satohisa & Tsuyoshi Saito

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  1. Tadahi Okada
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  2. Takumi Konno
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Correspondence to Takashi Kojima.

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Ethics Statement

The protocol for human study was reviewed and approved by the ethics committee of Sapporo Medical University School of Medicine. Written informed consent was obtained from each patient who participated in the investigation. All experiments were carried out in accordance with the approved guidelines and the Declaration of Helsinki.

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The authors declare that they have no competing interests.

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Tadahi Okada and Takumi Konno are equal first authors.

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Okada, T., Konno, T., Kohno, T. et al. Possibility of Targeting Claudin-2 in Therapy for Human Endometrioid Endometrial Carcinoma. Reprod. Sci. 27, 2092–2103 (2020). https://doi.org/10.1007/s43032-020-00230-6

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  • DOI: https://doi.org/10.1007/s43032-020-00230-6

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