Expression of Wnt4 in human pituitary adenomas regulates activation of the beta-catenin-independent pathway.
The Wnt signaling pathway has been implicated in the genesis of numerous human cancers. A member of the Wnt family of genes, Wnt4, has been known to regulate proliferation of anterior pituitary cell types in the mouse during embryonic development. In order to elucidate the roles of Wnt signaling in human pituitary adenomas, we examined the expression of Wnt4 and its putative receptor Frizzled6 (Fzd6) by immunohistochemistry in pituitary adenomas and normal pituitaries. Expression of Wnt4 was higher in growth hormone-producing adenomas (GHomas), prolactin-producing adenomas (PRLomas), and thyroid-stimulating hormone-producing adenomas (TSHomas) than in the normal pituitary. Fzd6 was widely expressed in GHomas, PRLomas, TSHomas, and gonadotropin subunit (GnSU)-positive adenomas. In normal pituitary glands, Wnt4 and Fzd6 were colocalized predominantly in follicle-stimulating hormone-, luteinizing hormone-, and alpha-subunits of glycoprotein hormone-positive cells. The canonical Wnt/beta-catenin signaling pathway was analyzed by beta-catenin immunohistochemistry. beta-Catenin was localized at the cell membrane in all pituitary adenomas, but not in the nuclei. On the other hand, Erk1/2 was highly activated in GHomas and TSHomas. These results suggested that activation of Wnt4/Fzd6 signaling through a "beta-catenin-independent" pathway played a role in proliferation and survival of the pituitary adenoma cells. Detailed involvement of transcription factors including Pit-1 remains to be further investigated.
Miyakoshi
Takashi
T
Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.
Takei
Mao
M
Kajiya
Hanako
H
Egashira
Noboru
N
Takekoshi
Susumu
S
Teramoto
Akira
A
Osamura
Robert Yoshiyuki
RY
D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D010902:Pituitary Gland / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060528:Wnt4 Protein; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; C484687:FZD6 protein, human; D051157:Frizzled Receptors; D043562:Receptors, G-Protein-Coupled; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D051176:beta Catenin