Impaired glycosylation of gastric mucins drives gastric tumorigenesis and serves as a novel therapeutic target.

GOLPH3 Golgi stress MAPK pathway Muc6 gastric cancer

Journal

Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630

Informations de publication

Date de publication:
05 Apr 2024
Historique:
received: 12 10 2023
revised: 10 03 2024
accepted: 24 03 2024
medline: 8 4 2024
pubmed: 8 4 2024
entrez: 7 4 2024
Statut: aheadofprint

Résumé

Gastric cancer is often accompanied by a loss of MUC6, but its pathogenic role in gastric carcinogenesis remains unclear. Muc6 knockout (Muc6-/-) mice and Muc6-dsRED mice were newly generated. Tff1Cre, Golph3-/-, R26-Golgi-mCherry, Hes1 Deletion of Muc6 in mice spontaneously causes pan-gastritis and invasive gastric cancers. Muc6-deficient tumor growth was dependent on MAPK activation, mediated by Golgi stress-induced upregulation of GOLPH3. Glycomic profiling revealed aberrant expression of mannose-rich N-linked glycans in gastric tumors, detected with Banana lectin in association with lack of MUC6 expression. We identified a precursor of clusterin as a binding partner of mannose glycans. MAPK activation, Golgi stress responses, aberrant mannose expression are found in a separate Cosmc- and A4gnt-deficient mouse models which lack normal O-glycosylation. Banana lectin-drug conjugates proved an effective treatment for mannose-rich murine and human gastric cancer. We propose that Golgi stress responses and aberrant glycans are important drivers of, and promising new therapeutic targets for gastric cancer.

Sections du résumé

BACKGROUND BACKGROUND
Gastric cancer is often accompanied by a loss of MUC6, but its pathogenic role in gastric carcinogenesis remains unclear.
METHOD METHODS
Muc6 knockout (Muc6-/-) mice and Muc6-dsRED mice were newly generated. Tff1Cre, Golph3-/-, R26-Golgi-mCherry, Hes1
RESULT RESULTS
Deletion of Muc6 in mice spontaneously causes pan-gastritis and invasive gastric cancers. Muc6-deficient tumor growth was dependent on MAPK activation, mediated by Golgi stress-induced upregulation of GOLPH3. Glycomic profiling revealed aberrant expression of mannose-rich N-linked glycans in gastric tumors, detected with Banana lectin in association with lack of MUC6 expression. We identified a precursor of clusterin as a binding partner of mannose glycans. MAPK activation, Golgi stress responses, aberrant mannose expression are found in a separate Cosmc- and A4gnt-deficient mouse models which lack normal O-glycosylation. Banana lectin-drug conjugates proved an effective treatment for mannose-rich murine and human gastric cancer.
CONCLUSION CONCLUSIONS
We propose that Golgi stress responses and aberrant glycans are important drivers of, and promising new therapeutic targets for gastric cancer.

Identifiants

DOI: 10.1053/j.gastro.2024.03.037 PMID: 38583723
pubmed: 38583723
pii: S0016-5085(24)00363-9
doi: 10.1053/j.gastro.2024.03.037
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.

Auteurs

Junya Arai (J)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Division of Gastroenterology, The Institute of Medical Science, Asahi Life Foundation, Tokyo, Japan.

Yoku Hayakawa (Y)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: yhayakawa-tky@umin.ac.jp.

Hiroaki Tateno (H)

Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan. Electronic address: h-tateno@aist.go.jp.

Keita Murakami (K)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Takeru Hayashi (T)

Division of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Masahiro Hata (M)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Yuki Matsushita (Y)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Hiroto Kinoshita (H)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Sohei Abe (S)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Ken Kurokawa (K)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Yukiko Oya (Y)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Mayo Tsuboi (M)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Sozaburo Ihara (S)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Ryota Niikura (R)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Nobumi Suzuki (N)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Yusuke Iwata (Y)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Toshiro Shiokawa (T)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Chihiro Shiomi (C)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Chie Uekura (C)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Keisuke Yamamoto (K)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Hiroaki Fujiwara (H)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Division of Gastroenterology, The Institute of Medical Science, Asahi Life Foundation, Tokyo, Japan.

Satoshi Kawamura (S)

Department of Gastroenterology, Graduate School of Medicine, University of Mie, Tokyo, Japan.

Hayato Nakagawa (H)

Department of Gastroenterology, Graduate School of Medicine, University of Mie, Tokyo, Japan.

Seiya Mizuno (S)

Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Laboratory Animal Science, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.

Takashi Kudo (T)

Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.

Satoru Takahashi (S)

Laboratory Animal Resource Center in Transborder Medical Research Center, and Department of Anatomy and Embryology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.

Tetsuo Ushiku (T)

Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Yoshihiro Hirata (Y)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Chifumi Fujii (C)

Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan; Department of Biotechnology, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan.

Jun Nakayama (J)

Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan.

Shinsuke Shibata (S)

Division of Microscopic Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.

Susan Woods (S)

Precision Cancer Medicine Theme, SAHMRI, Adelaide, South Australia, Australia; Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.

Daniel L Worthley (DL)

Colonoscopy Clinic, Brisbane, Queensland, Australia.

Masanori Hatakeyama (M)

Division of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Timothy C Wang (TC)

Division of Digestive and Liver disease, Department of Medicine, Columbia University, New York, New York.

Mitsuhiro Fujishiro (M)

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Classifications MeSH