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Impaired Glycosylation of Gastric Mucins Drives Gastric Tumorigenesis and Serves as a Novel Therapeutic Target.
Arai, Junya; Hayakawa, Yoku; Tateno, Hiroaki; Murakami, Keita; Hayashi, Takeru; Hata, Masahiro; Matsushita, Yuki; Kinoshita, Hiroto; Abe, Sohei; Kurokawa, Ken; Oya, Yukiko; Tsuboi, Mayo; Ihara, Sozaburo; Niikura, Ryota; Suzuki, Nobumi; Iwata, Yusuke; Shiokawa, Toshiro; Shiomi, Chihiro; Uekura, Chie; Yamamoto, Keisuke; Fujiwara, Hiroaki; Kawamura, Satoshi; Nakagawa, Hayato; Mizuno, Seiya; Kudo, Takashi; Takahashi, Satoru; Ushiku, Tetsuo; Hirata, Yoshihiro; Fujii, Chifumi; Nakayama, Jun; Shibata, Shinsuke; Woods, Susan; Worthley, Daniel L; Hatakeyama, Masanori; Wang, Timothy C; Fujishiro, Mitsuhiro.
Afiliación
  • 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.
  • Hayakawa Y; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Electronic address: yhayakawa-tky@umin.ac.jp.
  • 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.
  • Murakami K; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Hayashi T; Division of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Laboratory of Microbial Carcinogenesis, Institute of Microbial Chemistry, Microbial Chemistry Research Foundation, Tokyo, Japan.
  • Hata M; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Matsushita Y; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Kinoshita H; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Abe S; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Kurokawa K; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Oya Y; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Tsuboi M; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Ihara S; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Niikura R; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Suzuki N; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Iwata Y; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Shiokawa T; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Shiomi C; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Uekura C; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Yamamoto K; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • 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.
  • Kawamura S; Department of Gastroenterology, Graduate School of Medicine, Mie University, Mie, Japan.
  • Nakagawa H; Department of Gastroenterology, Graduate School of Medicine, Mie University, Mie, Japan.
  • 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.
  • 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.
  • 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.
  • Ushiku T; Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • Hirata Y; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
  • 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.
  • Nakayama J; Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan.
  • Shibata S; Division of Microscopic Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.
  • Woods S; Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia; Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.
  • Worthley DL; Colonoscopy Clinic, Brisbane, Queensland, Australia.
  • Hatakeyama M; Division of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; Laboratory of Microbial Carcinogenesis, Institute of Microbial Chemistry, Microbial Chemistry Research Foundation, Tokyo, Japan; Center of Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido U
  • Wang TC; Division of Digestive and Liver Disease, Department of Medicine, Columbia University, New York, New York.
  • Fujishiro M; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Gastroenterology ; 167(3): 505-521.e19, 2024 Aug.
Article en En | MEDLINE | ID: mdl-38583723
ABSTRACT
BACKGROUND &

AIMS:

Gastric cancer is often accompanied by a loss of mucin 6 (MUC6), but its pathogenic role in gastric carcinogenesis remains unclear.

METHODS:

Muc6 knockout (Muc6-/-) mice and Muc6-dsRED mice were newly generated. Tff1Cre, Golph3-/-, R26-Golgi-mCherry, Hes1flox/flox, Cosmcflox/flox, and A4gnt-/- mice were also used. Histology, DNA and RNA, proteins, and sugar chains were analyzed by whole-exon DNA sequence, RNA sequence, immunohistochemistry, lectin-binding assays, and liquid chromatography-mass spectrometry analysis. Gastric organoids and cell lines were used for in vitro assays and xenograft experiments.

RESULTS:

Deletion of Muc6 in mice spontaneously causes pan-gastritis and invasive gastric cancers. Muc6-deficient tumor growth was dependent on mitogen-activated protein kinase activation, mediated by Golgi stress-induced up-regulation of Golgi phosphoprotein 3. 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. Mitogen-activated protein kinase activation, Golgi stress responses, and aberrant mannose expression are found in separate Cosmc- and A4gnt-deficient mouse models that lack normal O-glycosylation. Banana lectin-drug conjugates proved an effective treatment for mannose-rich murine and human gastric cancer.

CONCLUSIONS:

We propose that Golgi stress responses and aberrant glycans are important drivers of and promising new therapeutic targets for gastric cancer.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Neoplasias Gástricas / Ratones Noqueados / Mucina 6 Límite: Animals / Humans Idioma: En Revista: Gastroenterology Año: 2024 Tipo del documento: Article País de afiliación: Japón
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Neoplasias Gástricas / Ratones Noqueados / Mucina 6 Límite: Animals / Humans Idioma: En Revista: Gastroenterology Año: 2024 Tipo del documento: Article País de afiliación: Japón