Therapeutic Potential of Dickkopf-1 in Wild-Type BRAF Papillary Thyroid Cancer via Regulation of β-Catenin/E-cadherin Signaling

• Published in: The journal of clinical endocrinology and metabolism 2014-09, Vol.99 (9), p.E1641-E1649
• Main Authors: Cho, Sun Wook, Kim, Young A, Sun, Hyun Jin, Ahn, Hwa Young, Lee, Eun Kyung, Yi, Ka Hee, Oh, Byung-Chul, Park, Do Joon, Cho, Bo Youn, Park, Young Joo
• Format: Article
• Language: English
• Subjects: Adult; Aged; Animals; beta Catenin - metabolism; Cadherins - metabolism; Carcinoma - genetics; Carcinoma - metabolism; Carcinoma, Papillary - genetics; Carcinoma, Papillary - metabolism; Cell Line, Tumor; Disease Models, Animal; Epithelial Cells - cytology; Female; Gene Expression Regulation, Neoplastic; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Male; Mice, Nude; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Thyroid Cancer, Papillary; Thyroid Gland - cytology; Thyroid Neoplasms - genetics; Thyroid Neoplasms - metabolism; Wnt Signaling Pathway - physiology; Xenograft Model Antitumor Assays
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2013-4467

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 BRAFWT patients had higher rates of aberrant expressions of β-catenin and E-cadherin than BRAFV600E patients. Indeed, the inhibitory effects of Dkk-1 on cell survival were more sensitive in BRAFWT (BHP10–3SC and TPC-1) than in BRAFV600E (SNU-790 and BCPAP) cells. Overexpression of BRAFV600E in normal thyroid epithelial (H tori) cells also reduced the effects of Dkk-1 on cell survival. Conclusion: 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 BRAFWT patients.