Down-regulation of FXYD3 expression in human lung cancers: its mechanism and potential role in carcinogenesis.
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.
Okudela
Koji
K
Department of Pathology, Yokohama City University Graduate School of Medicine, Kanazawa-Ku, Yokohama, Japan.
Yazawa
Takuya
T
Ishii
Jun
J
Woo
Tetsukan
T
Mitsui
Hideaki
H
Bunai
Tomoyasu
T
Sakaeda
Masashi
M
Shimoyamada
Hiroaki
H
Sato
Hanako
H
Tajiri
Michihiko
M
Ogawa
Nobuo
N
Masuda
Munetaka
M
Sugimura
Haruhiko
H
Kitamura
Hitoshi
H
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
C091777:FXYD3 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger