The Wnt/β-catenin pathway drives increased cyclin D1 levels in lymph node metastasis in papillary thyroid cancer.
We examined the expression of cyclin D1 in conjunction with β-catenin and the phosphorylated inactive form of glycogen synthase kinase 3β (GSK-3β) in benign, nonneoplastic thyroid tissue as well as papillary thyroid carcinoma primary tumors and nodal metastases. We aim to unravel the regulation of cyclin D1 and determine if this cell cycle protein is a useful biomarker for metastatic disease. It is clear that expression of cyclin D1 (P < .0001), β-catenin (P < .0001), and inactive form of GSK-3β (P < .0001) are significantly higher in papillary thyroid carcinoma primary tumors than in corresponding benign, nonneoplastic tissue thyroid specimens. Interestingly, β-catenin and cyclin D1 expressions in papillary thyroid carcinoma are correlated (P = .025), implying that β-catenin is a factor driving higher levels of cyclin D1 consistent with previous cell models linking Wnt/β-catenin signaling and cyclin D1 expression. Conversely, inactive form of GSK-3β expression does not correlate with cyclin D1 (P = .52) or β-catenin expression (P = .54). We also did not observe any relationship between tumor size and marker expression. Comparing papillary thyroid carcinoma primary tumors with or without nodal metastases, we did not see any differences in expression of inactive form of GSK-3β (P = .95), β-catenin (P = .14), or cyclin D1 (P = .46). However, in papillary thyroid carcinoma lymph node specimens, the up-regulation of cyclin D1 (P = .0083) was highly significant compared with primary tumors. pGSK-3β and β-catenin expression did not vary between primary tumors and nodal specimens. In conclusion, we have demonstrated that expression of cyclin D1 is linked to nodal metastases and that cyclin D1 levels are regulated by Wnt/β-catenin signaling. GSK pathway-mediated regulation of β-catenin or cyclin D1 expression does not appear operative in papillary thyroid carcinoma.
Department of Surgical Oncology, Cross Cancer Institute, Edmonton, Canada.
Jingdong
J
Zhang
Anthony J M
AJ
Gill
Joseph D
JD
Issacs
Bryn
B
Atmore
Amber
A
Johns
Leigh W
LW
Delbridge
Raymond
R
Lai
Todd P W
TP
McMullen
D014408:Biomarkers, Tumor / Q000378:metabolism; D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008207:Lymphatic Metastasis / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
D014408:Biomarkers, Tumor; D051176:beta Catenin; D019938:Cyclin D1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3