Sonic hedgehog acts as a negative regulator of {beta}-catenin signaling in the adult tongue epithelium.
Wnt/beta-catenin signaling has been implicated in taste papilla development; however, its role in epithelial maintenance and tumor progression in the adult tongue remains elusive. We show Wnt/beta-catenin pathway activation in reporter mice and by nuclear beta-catenin staining in the epithelium and taste papilla of adult mouse and human tongues. beta-Catenin activation in APC(min/+) mice, which carry a mutation in adenomatous poliposis coli (APC), up-regulates Sonic hedgehog (Shh) and Jagged-2 (JAG2) in the tongue epithelium without formation of squamous cell carcinoma (SCC). We demonstrate that Shh suppresses beta-catenin transcriptional activity in a signaling-dependent manner in vitro and in vivo. A similar regulation and function was observed for JAG2, suggesting that both pathways negatively regulate beta-catenin, thereby preventing SCC formation in the tongue. This was supported by reduced nuclear beta-catenin in the tongue epithelium of Patched(+/-) mice, exhibiting dominant active Shh signaling. At the invasive front of human tongue cancer, nuclear beta-catenin and Shh were increased, suggesting their participation in tumor progression. Interestingly, Shh but not JAG2 was able to reduce beta-catenin signaling in SCC cells, arguing for a partial loss of negative feedback on beta-catenin transcription in tongue cancer. We show for the first time that the putative Wnt/beta-catenin targets Shh and JAG2 control beta-catenin signaling in the adult tongue epithelium, a function that is partially lost in lingual SCC.
Institute of Neurology (Edinger-Institute), Johann Wolfgang Goethe-University Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Fabian T
FT
Schneider
Anne
A
Schänzer
Cathrin J
CJ
Czupalla
Sonja
S
Thom
Knut
K
Engels
Mirko H H
MHH
Schmidt
Karl H
KH
Plate
Stefan
S
Liebner
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D004848:Epithelium / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072101:Jagged-2 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D015398:Signal Transduction / Q000502:physiology*; D014059:Tongue / Q000033:anatomy & histology*; D014062:Tongue Neoplasms / Q000378:metabolism / Q000473:pathology; D015533:Transcriptional Activation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; C490504:JAG2 protein, human; C490503:Jag2 protein, mouse; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; C509239:SHH protein, human; C465570:Shh protein, mouse; D051176:beta Catenin