Therapeutic Potential of Dickkopf-1 in Wild-Type BRAF Papillary Thyroid Cancer via Regulation of beta-Catenin/E-cadherin Signaling
- 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
- Issue Date
- Sep-2014
- Publisher
- ENDOCRINE SOC
- Citation
- JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, v.99, no.9, pp E1641 - E1649
- Journal Title
- JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
- Volume
- 99
- Number
- 9
- Start Page
- E1641
- End Page
- E1649
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/11880
- DOI
- 10.1210/jc.2013-4467
- ISSN
- 0021-972X
1945-7197
- Abstract
- Background: Aberrant activation of the Wnt/beta-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 beta-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 beta-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 beta-catenin expression compared to membranous-dominant expression in normal tissues. Aberrant beta-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 beta-catenin and E-cadherin expressions. Furthermore, tissue microarray analysis demonstrated that BRAF(WT) patients had higher rates of aberrant expressions of beta-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. Conclusion: A subset of PTC patients showed aberrant expression of beta-catenin/E-cadherin signaling and poor disease-free survival. Dkk-1 might have a therapeutic role, particularly in BRAF(WT) patients.
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