title: Down-regulation of FXYD3 expression in human lung cancers: its mechanism and potential role in carcinogenesis.
abstract: FXYD3 is a FXYD-containing Na,K-ATPase ion channel regulator first identified as a protein overexpressed in murine breast tumors initiated by oncogenic ras or neu. However, our preliminary study revealed that FXYD3 expression was down-regulated in oncogenic KRAS-transduced airway epithelial cells. This contradiction led us to investigate the role of FXYD3 in carcinogenesis of the lung. FXYD3 mRNA and protein levels were lower in most of the lung cancer cell lines than in either the noncancerous lung tissue or airway epithelial cells. Protein levels were also lower in a considerable proportion of primary lung cancers than in nontumoral airway epithelia; FXYD3 expression levels decreased in parallel with the dedifferentiation process. Also, a somatic point mutation, g55c (D19H), was found in one cell line. Forced expression of the wild-type FXYD3, but not the mutant, restored the well-demarcated distribution of cortical actin in cancer cells that had lost FXYD3 expression, suggesting FXYD3 plays a role in the maintenance of cytoskeletal integrity. However, no association between FXYD3 expression and its promoter's methylation status was observed. Therefore, inactivation of FXYD3 through a gene mutation or unknown mechanism could be one cause of the atypical shapes of cancer cells and play a potential role in the progression of lung cancer.
authors.affiliation: Department of Pathology, Yokohama City University Graduate School of Medicine, Kanazawa-Ku, Yokohama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Okudela
authors.forename: Takuya
authors.initials: T
authors.lastname: Yazawa
authors.forename: Jun
authors.initials: J
authors.lastname: Ishii
authors.forename: Tetsukan
authors.initials: T
authors.lastname: Woo
authors.forename: Hideaki
authors.initials: H
authors.lastname: Mitsui
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Bunai
authors.forename: Masashi
authors.initials: M
authors.lastname: Sakaeda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimoyamada
authors.forename: Hanako
authors.initials: H
authors.lastname: Sato
authors.forename: Michihiko
authors.initials: M
authors.lastname: Tajiri
authors.forename: Nobuo
authors.initials: N
authors.lastname: Ogawa
authors.forename: Munetaka
authors.initials: M
authors.lastname: Masuda
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sugimura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kitamura
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C091777:FXYD3 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger