Impaired Glycosylation of Gastric Mucins Drives Gastric Tumorigenesis and Serves as a Novel Therapeutic Target.
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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
Аннотация
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.