Alternative Title胃癌におけるクローディン4標的化によるシスプラチン化学療法感受性の向上
Note (General)type:Thesis
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.
博士（医学）・甲第713号・令和元年6月26日
Copyright: Nishiguchi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CCBY 3.0 https://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
identifier:Oncotarget Vol.10 No.22 p.2189-2202 (2019 Mar)
identifier:19492553
identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/3585
identifier:Oncotarget, 10(22): 2189-2202
DOIinfo:doi/10.18632/oncotarget.26758
Collection (particular)国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文
Date Accepted (W3CDTF)2019-10-04T14:36:02+09:00
Data Provider (Database)国立国会図書館 : 国立国会図書館デジタルコレクション