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Gastric Cancer
Erschienen in:

04.06.2022 | Original Article

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

verfasst von: 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 Torisu, Takanari Kitazono, Tomohiro Kanayama, Hiroyuki Tomita, Yoshinao Oda, Hitoshi Kusaba, Takahiro Maeda, Koichi Akashi, Eishi Baba

Erschienen in: Gastric Cancer | Ausgabe 5/2022

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Abstract

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.
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Metadaten
Titel
Potential therapeutic targets discovery by transcriptome analysis of an in vitro human gastric signet ring carcinoma model
verfasst von
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 Torisu
Takanari Kitazono
Tomohiro Kanayama
Hiroyuki Tomita
Yoshinao Oda
Hitoshi Kusaba
Takahiro Maeda
Koichi Akashi
Eishi Baba
Publikationsdatum
04.06.2022
Verlag
Springer Nature Singapore
Erschienen in
Gastric Cancer / Ausgabe 5/2022
Print ISSN: 1436-3291
Elektronische ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-022-01307-8

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