Oncotarget

Research Papers:

Targeting claudin-4 enhances CDDP-chemosensitivity in gastric cancer

Yukiko Nishiguchi _, Rina Fujiwara-Tani, Takamitsu Sasaki, Yi Luo, Hitoshi Ohmori, Shingo Kishi, Shiori Mori, Kei Goto, Wataru Yasui, Masayuki Sho and Hiroki Kuniyasu

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Oncotarget. 2019; 10:2189-2202. https://doi.org/10.18632/oncotarget.26758

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Abstract

Yukiko Nishiguchi1,2, Rina Fujiwara-Tani1, Takamitsu Sasaki1, Yi Luo1,3, Hitoshi Ohmori1, Shingo Kishi1, Shiori Mori1, Kei Goto1, Wataru Yasui4, Masayuki Sho2 and Hiroki Kuniyasu1

1Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan

2Department of Surgery, Nara Medical University, Kashihara, Nara 634-8522, Japan

3Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China

4Department of Molecular Pathology, Hiroshima University Graduate School, Hiroshima 734-8551, Japan

Correspondence to:

Hiroki Kuniyasu, email: cooninh@zb4.so-net.ne.jp

Masayuki Sho, email: m-sho@naramed-u.ac.jp

Keywords: claudin; tight junction

Received: November 03, 2018     Accepted: February 22, 2019     Published: March 15, 2019

ABSTRACT

Claudins are major tight-junction proteins that mediate cellular polarity and differentiation. The present study investigated whether the 4D3 antibody to the human CLDN4 extracellular domain (that we previously established) is capable of modulating chemotherapeutic sensitivity in gastric cancer (GC). The results of the present study showed that CLDN4 was overexpressed in 137 of the 192 analyzed GC cases, and that CLDN4 expression was retained in tumors of a lower histological grade (more differentiated), and/or those that were caudal-type homeobox protein 2 (CDX2)-positive, but was reduced in more highly undifferentiated, and CDX2-negative GC cases. The study also compared the synergic effects of combining 4D3 with CDDP treatment and knocking down CLDN4 expression in MKN74 and TMK-1 human GC cells. Co-treatment with 4D3 increased anti-tumor effects of CDDP, whereas CLDN4 knockdown did not. In the TMK-1 cells, non-tight junction CLDN4 associated with integrin β1, increasing stem cell-associated proteins via FAK-c-SRC signals. The anti-tumoral effect of CDDP and 4D3 was examined in a nude mouse subcutaneous tumor model. In the two GC cell lines, concurrent treatment with 4D3 and CDDP synergistically inhibited cell proliferation and increased tumor necrosis and apoptosis to a greater degree than CDDP treatment alone. These findings suggest that 4D3 might increase chemotherapeutic sensitivity by evoking structural disintegration of tight-junction CLDN4 expressed in gastric cancer.


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