title: Interaction of Muc4 and ErbB2 in a transgenic mouse model of gallbladder carcinoma: potential pathobiological implications.
abstract: The molecular mechanism of gallbladder carcinogenesis and cancer growth remains unknown. BK5.erbB2 transgenic mice in which erbB2 is overexpressed and activated in the biliary epithelia develop adenocarcinoma of the gallbladder at a high incidence. Although it has been reported that erbB2 plays an important role in tumorigenesis, little is known about the involvement of its ligand(s). The expression level of Muc4, a potential functional ligand for erbB2, and its interaction with erbB2 in the gallbladder of BK5.erbB2 mice were determined. By immunohistochemistry and in situ hybridization, both Muc4 mRNA and protein levels were strongly expressed in the cancerous epithelia of gallbladder from BK5.erbB2 mice. Also, in the hyperplastic (precancerous) epithelia, the protein levels were modestly expressed. Immunostaining with Muc4 (ASGP2) Ab overlapped with that with erbB2 Ab in the apical membranous components of the cancerous epithelia, indicating the co-localization of Muc4 and erbB2. Immunoprecipitation experiments revealed an interaction between Muc4 and erbB2 in the gallbladders. The interaction was associated with the hyperphosphorylation of erbB2, MAPK and Akt, and also with the overexpression of cyclooxygenase-2. However, in other organs that overexpressed erbB2 (trachea, esophagus and forestomach), Muc4 was expressed in only trace or modest amounts, and erbB2 was not hyperphosphorylated. Collectively, Muc4 is upregulated and interacts with erbB2 in gallbladders from BK5.erbB2 mice. It is likely that Muc4 plays an important role during gallbladder carcinogenesis and/or cancer growth by potentiating erbB2 signaling.
authors.affiliation: Department of Gastroenterology, Ushiku-Aiwa General Hospital, Ushiku, Ibaraki, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyahara
authors.affiliation: Division of Medical Science, Faculty of Medicine, University of Tsukuba, Tsukuba-shi, Ibaraki, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Shoda
authors.affiliation: Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: Department of Gastroenterology, National Hospital Organization Mito Medical Center, Ibaraki-machi, Ibaraki, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ishida
authors.affiliation: Department of Pharmaceutical Research, Mitsubishi Kagaku Bio‑Clinical Laboratories, Inc., Itabashi-ku, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ueda
authors.affiliation: Department of Anatomy, Kyorin University School of Medicine, Mitaka‑shi, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Akimoto
authors.affiliation: Department of Anatomy, Kyorin University School of Medicine, Mitaka‑shi, Tokyo, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Kawakami
authors.affiliation: Institute for Medical Innovation, St. Luke's International Medical Center, Chuo-ku, Tokyo, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Irimura
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D005706:Gallbladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D055264:Mucin-4 / Q000235:genetics* / Q000378:metabolism*; D009374:Neoplasms, Experimental; D009928:Organ Specificity; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D055264:Mucin-4; D018719:Erb-b2 Receptor Tyrosine Kinases; C524659:Muc4 protein, mouse; C524056:Erbb2 protein, mouse