%0 Journal Article
%T Impaired Glycosylation of Gastric Mucins Drives Gastric Tumorigenesis and Serves as a Novel Therapeutic Target.
%A Arai J
%A Hayakawa Y
%A Tateno H
%A Murakami K
%A Hayashi T
%A Hata M
%A Matsushita Y
%A Kinoshita H
%A Abe S
%A Kurokawa K
%A Oya Y
%A Tsuboi M
%A Ihara S
%A Niikura R
%A Suzuki N
%A Iwata Y
%A Shiokawa T
%A Shiomi C
%A Uekura C
%A Yamamoto K
%A Fujiwara H
%A Kawamura S
%A Nakagawa H
%A Mizuno S
%A Kudo T
%A Takahashi S
%A Ushiku T
%A Hirata Y
%A Fujii C
%A Nakayama J
%A Shibata S
%A Woods S
%A Worthley DL
%A Hatakeyama M
%A Wang TC
%A Fujishiro M
%J Gastroenterology
%V 167
%N 3
%D 2024 Aug 6
%M 38583723
%F 33.883
%R 10.1053/j.gastro.2024.03.037
%X <B>OBJECTIVE: </B>Gastric cancer is often accompanied by a loss of mucin 6 (MUC6), but its pathogenic role in gastric carcinogenesis remains unclear.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>We propose that Golgi stress responses and aberrant glycans are important drivers of and promising new therapeutic targets for gastric cancer.