Therapeutic potential of Dickkopf-1 in wild-type BRAF papillary thyroid cancer via regulation of β-catenin/E-cadherin signaling.
BACKGROUND
Aberrant activation of the Wnt/β-catenin pathway is a common pathogenesis of various human cancers. We investigated the role of the Wnt inhibitor, Dkk-1, in papillary thyroid cancer (PTC).


METHODS
Immunohistochemical β-catenin staining was performed in tissue microarray containing 148 PTCs and five normal thyroid tissues. In vivo effects of Dkk-1 were explored using ectopic tumors with BHP10-3SC cells.


RESULTS
In 27 PTC patients, 60% of patients showed β-catenin up-regulation and Dkk-1 down-regulation in tumor vs normal tissues. Tissue microarray analysis showed that 14 of 148 PTC samples exhibited cytoplasmic-dominant β-catenin expression compared to membranous-dominant expression in normal tissues. Aberrant β-catenin expression was significantly correlated with higher rates of the loss of membranous E-cadherin expression and poor disease-free survival than that in the normal membranous expression group over a median follow-up period of 14 years. Implantation of Dkk-1-overexpressing BHP10-3SC cells revealed delayed tumor growth, resulting from the rescue of membranous β-catenin and E-cadherin expressions. Furthermore, tissue microarray analysis demonstrated that BRAF(WT) patients had higher rates of aberrant expressions of β-catenin and E-cadherin than BRAF(V600E) patients. Indeed, the inhibitory effects of Dkk-1 on cell survival were more sensitive in BRAF(WT) (BHP10-3SC and TPC-1) than in BRAF(V600E) (SNU-790 and BCPAP) cells. Overexpression of BRAF(V600E) in normal thyroid epithelial (H tori) cells also reduced the effects of Dkk-1 on cell survival.


CONCLUSIONS
A subset of PTC patients showed aberrant expression of β-catenin/E-cadherin signaling and poor disease-free survival. Dkk-1 might have a therapeutic role, particularly in BRAF(WT) patients.
Department of Internal Medicine (S.W.C., H.Y.A., D.J.P., B.Y.C., Y.J.P.), Seoul National University College of Medicine, Seoul 110-744, Korea; Department of Internal Medicine (S.W.C., H.J.S.), National Medical Center, Seoul 110-799, Korea; Departments of Pathology (Y.A.K.) and Internal Medicine (K.H.Y.), Seoul National University Boramae Medical Center, Seoul 156-707, Korea; Department of Internal Medicine (H.Y.A., B.Y.C.), Chung-Ang University Hospital, Seoul 156-755, Korea; Lee Gil Ya Cancer and Diabetes Institute (B-C.O.), Gachon University Graduate School of Medicine, Incheon 405-760, Korea; and Center for Thyroid Cancer (E.K.L.), National Cancer Center, Gyeonggi-do 410-769, Korea.
Sun Wook
SW
Cho
Young A
YA
Kim
Hyun Jin
HJ
Sun
Hwa Young
HY
Ahn
Eun Kyung
EK
Lee
Ka Hee
KH
Yi
Byung-Chul
BC
Oh
Do Joon
DJ
Park
Bo Youn
BY
Cho
Young Joo
YJ
Park
D000328:Adult; D000368:Aged; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000166:cytology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; C501126:DKK1 protein, human; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051176:beta Catenin; C482119:BRAF protein, human; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf