Potential therapeutic targets discovery by transcriptome analysis of an in vitro human gastric signet ring carcinoma model

Kyoko Yamaguchi, Tomoyasu Yoshihiro, Hiroshi Ariyama, Mamoru Ito, Michitaka Nakano, Yuichiro Semba, Jumpei Nogami, Kenji Tsuchihashi, Takuji Yamauchi, Shohei Ueno, Taichi Isobe, Koji Shindo, Taiki Moriyama, Kenoki Ohuchida, Masafumi Nakamura, Yoshihiro Nagao, Tetsuo Ikeda, Makoto Hashizume, Hiroyuki Konomi, Takehiro TorisuTakanari Kitazono, Tomohiro Kanayama, Hiroyuki Tomita, Yoshinao Oda, Hitoshi Kusaba, Takahiro Maeda, Koichi Akashi, Eishi Baba

研究成果: ジャーナルへの寄稿学術誌査読

抄録

BACKGROUND: Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development.

METHODS: To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO).

RESULTS: CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area.

CONCLUSIONS: E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.

本文言語英語
ジャーナルGastric Cancer
DOI
出版ステータス印刷前の電子出版 - 6月 4 2022

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