{Reference Type}: Journal Article
{Title}: Impaired Glycosylation of Gastric Mucins Drives Gastric Tumorigenesis and Serves as a Novel Therapeutic Target.
{Author}: Arai J;Hayakawa Y;Tateno H;Murakami K;Hayashi T;Hata M;Matsushita Y;Kinoshita H;Abe S;Kurokawa K;Oya Y;Tsuboi M;Ihara S;Niikura R;Suzuki N;Iwata Y;Shiokawa T;Shiomi C;Uekura C;Yamamoto K;Fujiwara H;Kawamura S;Nakagawa H;Mizuno S;Kudo T;Takahashi S;Ushiku T;Hirata Y;Fujii C;Nakayama J;Shibata S;Woods S;Worthley DL;Hatakeyama M;Wang TC;Fujishiro M;
{Journal}: Gastroenterology
{Volume}: 167
{Issue}: 3
{Year}: 2024 Aug 6
{Factor}: 33.883
{DOI}: 10.1053/j.gastro.2024.03.037
{Abstract}: <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.