Frequent hypermethylation of WNT pathway genes in laryngeal squamous cell carcinomas.
BACKGROUND
Aberrations in the function of the WNT signaling pathway have been recently implicated in the pathogenesis of head and neck cancer, and the hypermethylation of several WNT cascade inhibitors were shown to be useful in disease prognosis. However, the extent of deregulation of WNT pathway by DNA hypermethylation has not been studied in detail in laryngeal cancer so far. The aim of this study was to establish the frequency of methylation of WNT pathway negative regulators in laryngeal squamous cell carcinomas and evaluate its prognostic significance.


METHODS
Twenty-six laryngeal squamous cell carcinoma cell lines and samples obtained from twenty-eight primary laryngeal carcinoma patients were analyzed. The methylation status of DKK1, LKB1, PPP2R2B, RUNX3, SFRP1, SFRP2, and WIF-1 was assessed using the methylation-specific polymerase chain reaction.


RESULTS
Frequent hypermethylation of DKK1, PPP2R2B, SFRP1, SFRP2, and WIF-1 was detected, and a high methylation index was usually observed. Half of the cell lines analyzed and seventy percent of primary laryngeal carcinoma cases were characterized by the methylation of at least four genes. The hypermethylation of PPP2R2B or WIF-1 was associated with longer survival in laryngeal carcinoma cell lines. Moreover, the concurrent methylation of PPP2R2B and SFRP1 differentiated primary from recurrent laryngeal carcinoma cell lines.


CONCLUSIONS
Frequent hypermethylation of WNT pathway negative regulators is observed in laryngeal squamous cell carcinomas. The possible prognostic significance of the methylation of DKK1, PPP2R2B, and SFRP1 needs to be evaluated in further prospective studies.
Department of Pharmaceutical Biochemistry, Poznań University of Medical Sciences, Poznań, Poland.
Jarosław
J
Paluszczak
Dawid
D
Hemmerling
Magdalena
M
Kostrzewska-Poczekaj
Małgorzata
M
Jarmuż-Szymczak
Reidar
R
Grenman
Małgorzata
M
Wierzbicka
Wanda
W
Baer-Dubowska
D000091162:AMP-Activated Protein Kinase Kinases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000556:secondary; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007822:Laryngeal Neoplasms / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D012097:Repressor Proteins / Q000235:genetics; D015996:Survival Rate; D060449:Wnt Signaling Pathway / Q000235:genetics*; D000094742:Secreted Frizzled-Related Proteins
D000091162:AMP-Activated Protein Kinase Kinases; D048868:Adaptor Proteins, Signal Transducing; D050677:Core Binding Factor Alpha 3 Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D012097:Repressor Proteins; C501126:DKK1 protein, human; C493729:Runx3 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C109618:SFRP2 protein, human; C485569:WIF1 protein, human; C109790:STK11 protein, human; C505936:PPP2R2B protein, human
DNA methylation; WNT pathway; epimarker; laryngeal cancer