Elucidation of the mechanism of carcinogenic transformation of human gastric epithelial cells in atrophic gastritis

Tomoyasu Yoshihiro; Kyoko Yamaguchi; Hiroshi Ariyama; Sakuya Koreishi; Koki Uehara; Hirofumi Ohmura; Mamoru Ito; Kenji Tsuchihashi; Taichi Isobe; Koji Shindo; Kenoki Ohuchida; Masafumi Nakamura; Yoshihiro Nagao; Yoshinao Oda; Koichi Akashi; Eishi Baba

doi:10.1016/j.bbadis.2025.167843

Elucidation of the mechanism of carcinogenic transformation of human gastric epithelial cells in atrophic gastritis

Tomoyasu Yoshihiro, Kyoko Yamaguchi, Hiroshi Ariyama, Sakuya Koreishi, Koki Uehara, Hirofumi Ohmura, Mamoru Ito, Kenji Tsuchihashi, Taichi Isobe, Koji Shindo, Kenoki Ohuchida, Masafumi Nakamura, Yoshihiro Nagao, Yoshinao Oda, Koichi Akashi, Eishi Baba

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Helicobacter pylori infection and subsequent atrophic gastritis (AG) and intestinal metaplasia (IM) are regarded as precursor conditions for gastric cancer (GC). Though diverse mechanisms of carcinogenesis from AG and IM have been clarified using mouse models, few studies using human models have been reported. Here, we describe in vitro modeling of IM, as well as in vivo modeling of the oncogenic transformation from AG using human gastric organoids.

METHODS: Organoids derived from patients with AG were established and characterized by immunohistochemistry and in situ hybridization. Niche factor withdrawal and genetic engineering using CRISPR/Cas9 were conducted for modeling IM, and manipulated organoids were xenografted subcutaneously in mice to establish a GC model.

RESULTS: AG organoids (AGOs) were maintained by Wnt niche factors; withdrawal of these factors led to differentiation toward foveolar cells. Knockout of Runt-related transcription factor 3 (RUNX3), or activation of bone morphogenetic protein (BMP) signaling, resulted in accumulation of the key IM markers caudal-type homeobox 2 (CDX2) and mucin 2 (MUC2) in AGOs; disruption of SMAD4 counteracted the induction of these markers. Organoids doubly deficient for TP53 and SMAD4 formed larger and more proliferative p21 -negative subcutaneous tumors than did RUNX3-deficient organoids, suggesting that induction of a senescent state is a key barrier in stepwise carcinogenesis from AG.

CONCLUSIONS: Wnt signaling is essential for homeostasis of AG, and SMAD4-dependent activation of BMP signaling promotes intestinal differentiation. Combined disruption of TP53 and SMAD4 confers tumorigenic potential to AGOs by inhibiting p21 induction.

Original language	English
Pages (from-to)	167843
Journal	Biochimica et Biophysica Acta - Molecular Basis of Disease
DOIs	https://doi.org/10.1016/j.bbadis.2025.167843
Publication status	E-pub ahead of print - Apr 10 2025

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10.1016/j.bbadis.2025.167843

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Yoshihiro, T., Yamaguchi, K., Ariyama, H., Koreishi, S., Uehara, K., Ohmura, H., Ito, M., Tsuchihashi, K., Isobe, T., Shindo, K., Ohuchida, K., Nakamura, M., Nagao, Y., Oda, Y., Akashi, K., & Baba, E. (2025). Elucidation of the mechanism of carcinogenic transformation of human gastric epithelial cells in atrophic gastritis. Biochimica et Biophysica Acta - Molecular Basis of Disease, 167843. Advance online publication. https://doi.org/10.1016/j.bbadis.2025.167843

Yoshihiro, T, Yamaguchi, K, Ariyama, H, Koreishi, S, Uehara, K, Ohmura, H , Ito, M , Tsuchihashi, K , Isobe, T, Shindo, K, Ohuchida, K, Nakamura, M, Nagao, Y, Oda, Y , Akashi, K & Baba, E 2025, 'Elucidation of the mechanism of carcinogenic transformation of human gastric epithelial cells in atrophic gastritis', Biochimica et Biophysica Acta - Molecular Basis of Disease, pp. 167843. https://doi.org/10.1016/j.bbadis.2025.167843

@article{234171cf71114ad6ad079f71cd83f69d,

title = "Elucidation of the mechanism of carcinogenic transformation of human gastric epithelial cells in atrophic gastritis",

abstract = "BACKGROUND: Helicobacter pylori infection and subsequent atrophic gastritis (AG) and intestinal metaplasia (IM) are regarded as precursor conditions for gastric cancer (GC). Though diverse mechanisms of carcinogenesis from AG and IM have been clarified using mouse models, few studies using human models have been reported. Here, we describe in vitro modeling of IM, as well as in vivo modeling of the oncogenic transformation from AG using human gastric organoids.METHODS: Organoids derived from patients with AG were established and characterized by immunohistochemistry and in situ hybridization. Niche factor withdrawal and genetic engineering using CRISPR/Cas9 were conducted for modeling IM, and manipulated organoids were xenografted subcutaneously in mice to establish a GC model.RESULTS: AG organoids (AGOs) were maintained by Wnt niche factors; withdrawal of these factors led to differentiation toward foveolar cells. Knockout of Runt-related transcription factor 3 (RUNX3), or activation of bone morphogenetic protein (BMP) signaling, resulted in accumulation of the key IM markers caudal-type homeobox 2 (CDX2) and mucin 2 (MUC2) in AGOs; disruption of SMAD4 counteracted the induction of these markers. Organoids doubly deficient for TP53 and SMAD4 formed larger and more proliferative p21 -negative subcutaneous tumors than did RUNX3-deficient organoids, suggesting that induction of a senescent state is a key barrier in stepwise carcinogenesis from AG.CONCLUSIONS: Wnt signaling is essential for homeostasis of AG, and SMAD4-dependent activation of BMP signaling promotes intestinal differentiation. Combined disruption of TP53 and SMAD4 confers tumorigenic potential to AGOs by inhibiting p21 induction.",

author = "Tomoyasu Yoshihiro and Kyoko Yamaguchi and Hiroshi Ariyama and Sakuya Koreishi and Koki Uehara and Hirofumi Ohmura and Mamoru Ito and Kenji Tsuchihashi and Taichi Isobe and Koji Shindo and Kenoki Ohuchida and Masafumi Nakamura and Yoshihiro Nagao and Yoshinao Oda and Koichi Akashi and Eishi Baba",

note = "Copyright {\textcopyright} 2024. Published by Elsevier B.V.",

year = "2025",

month = apr,

day = "10",

doi = "10.1016/j.bbadis.2025.167843",

language = "English",

pages = "167843",

journal = "Biochimica et Biophysica Acta - Molecular Basis of Disease",

issn = "0925-4439",

publisher = "Elsevier B.V.",

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TY - JOUR

T1 - Elucidation of the mechanism of carcinogenic transformation of human gastric epithelial cells in atrophic gastritis

AU - Yoshihiro, Tomoyasu

AU - Yamaguchi, Kyoko

AU - Ariyama, Hiroshi

AU - Koreishi, Sakuya

AU - Uehara, Koki

AU - Ohmura, Hirofumi

AU - Ito, Mamoru

AU - Tsuchihashi, Kenji

AU - Isobe, Taichi

AU - Shindo, Koji

AU - Ohuchida, Kenoki

AU - Nakamura, Masafumi

AU - Nagao, Yoshihiro

AU - Oda, Yoshinao

AU - Akashi, Koichi

AU - Baba, Eishi

PY - 2025/4/10

Y1 - 2025/4/10

N2 - BACKGROUND: Helicobacter pylori infection and subsequent atrophic gastritis (AG) and intestinal metaplasia (IM) are regarded as precursor conditions for gastric cancer (GC). Though diverse mechanisms of carcinogenesis from AG and IM have been clarified using mouse models, few studies using human models have been reported. Here, we describe in vitro modeling of IM, as well as in vivo modeling of the oncogenic transformation from AG using human gastric organoids.METHODS: Organoids derived from patients with AG were established and characterized by immunohistochemistry and in situ hybridization. Niche factor withdrawal and genetic engineering using CRISPR/Cas9 were conducted for modeling IM, and manipulated organoids were xenografted subcutaneously in mice to establish a GC model.RESULTS: AG organoids (AGOs) were maintained by Wnt niche factors; withdrawal of these factors led to differentiation toward foveolar cells. Knockout of Runt-related transcription factor 3 (RUNX3), or activation of bone morphogenetic protein (BMP) signaling, resulted in accumulation of the key IM markers caudal-type homeobox 2 (CDX2) and mucin 2 (MUC2) in AGOs; disruption of SMAD4 counteracted the induction of these markers. Organoids doubly deficient for TP53 and SMAD4 formed larger and more proliferative p21 -negative subcutaneous tumors than did RUNX3-deficient organoids, suggesting that induction of a senescent state is a key barrier in stepwise carcinogenesis from AG.CONCLUSIONS: Wnt signaling is essential for homeostasis of AG, and SMAD4-dependent activation of BMP signaling promotes intestinal differentiation. Combined disruption of TP53 and SMAD4 confers tumorigenic potential to AGOs by inhibiting p21 induction.

AB - BACKGROUND: Helicobacter pylori infection and subsequent atrophic gastritis (AG) and intestinal metaplasia (IM) are regarded as precursor conditions for gastric cancer (GC). Though diverse mechanisms of carcinogenesis from AG and IM have been clarified using mouse models, few studies using human models have been reported. Here, we describe in vitro modeling of IM, as well as in vivo modeling of the oncogenic transformation from AG using human gastric organoids.METHODS: Organoids derived from patients with AG were established and characterized by immunohistochemistry and in situ hybridization. Niche factor withdrawal and genetic engineering using CRISPR/Cas9 were conducted for modeling IM, and manipulated organoids were xenografted subcutaneously in mice to establish a GC model.RESULTS: AG organoids (AGOs) were maintained by Wnt niche factors; withdrawal of these factors led to differentiation toward foveolar cells. Knockout of Runt-related transcription factor 3 (RUNX3), or activation of bone morphogenetic protein (BMP) signaling, resulted in accumulation of the key IM markers caudal-type homeobox 2 (CDX2) and mucin 2 (MUC2) in AGOs; disruption of SMAD4 counteracted the induction of these markers. Organoids doubly deficient for TP53 and SMAD4 formed larger and more proliferative p21 -negative subcutaneous tumors than did RUNX3-deficient organoids, suggesting that induction of a senescent state is a key barrier in stepwise carcinogenesis from AG.CONCLUSIONS: Wnt signaling is essential for homeostasis of AG, and SMAD4-dependent activation of BMP signaling promotes intestinal differentiation. Combined disruption of TP53 and SMAD4 confers tumorigenic potential to AGOs by inhibiting p21 induction.

U2 - 10.1016/j.bbadis.2025.167843

DO - 10.1016/j.bbadis.2025.167843

M3 - Article

C2 - 40220876

SN - 0925-4439

SP - 167843

JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

ER -

Elucidation of the mechanism of carcinogenic transformation of human gastric epithelial cells in atrophic gastritis

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