Epigenetic inactivation of SFRP genes in oral squamous cell carcinoma.
Although mutations of APC, CTNNB1 (beta-catenin) and AXIN1 are rare in oral squamous cell carcinoma (OSCC), activation of the Wnt signaling pathway is thought to play an important role in oral carcinogenesis. In the present study, we examined the relationship between Wnt signaling and epigenetic alteration of the secreted frizzled-related protein (SFRP) genes in OSCC. We frequently detected loss of membrane localization of beta-catenin and its cytoplasmic or nuclear accumulation in OSCC cell lines, although these cell lines showed no APC or CTNNB1 (beta-catenin) mutations and no methylation of CDH1 (E-cadherin). By contrast, we frequently detected methylation of SFRP1 (7/17, 41%) SFRP2 (16/17, 94%) and SFRP5 (14/17, 82%) in a panel of OSCC cell lines, as well as in specimens of primary tumors collected from 44 OSCC patients (SFRP1, 10/42, 24%; SFRP2, 16/44, 36%; SFRP5, 7/43, 16%). We also observed that OSCC cell lines express various Wnt ligands, and that ectopic expression of SFRPs inhibited cancer cell proliferation. Our results confirm the frequent methylation and silencing of SFRP genes in OSCC, and suggest that their loss of function contributes to activation of Wnt signaling that leads to cell proliferation during oral carcinogenesis.
Sogabe
Yohei
Y
Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, S1, W16, Sapporo 060-8543, Japan.
Suzuki
Hiromu
H
Toyota
Minoru
M
Ogi
Kazuhiro
K
Imai
Takashi
T
Nojima
Masanori
M
Sasaki
Yasushi
Y
Hiratsuka
Hiroyoshi
H
Tokino
Takashi
T
D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000368:Aged; D015703:Antigens, CD; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D051153:Wnt Proteins; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D015703:Antigens, CD; D015820:Cadherins; D005136:Eye Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C109618:SFRP2 protein, human; C118511:SFRP5 protein, human