Sun Wook Cho1, Young A Kim, Hyun Jin Sun, Hwa Young Ahn, Eun Kyung Lee, Ka Hee Yi, Byung-Chul Oh, Do Joon Park, Bo Youn Cho, Young Joo Park. 1. 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.
Abstract
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. 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 BRAF(WT) patients.
BACKGROUND: Aberrant activation of the Wnt/β-catenin pathway is a common pathogenesis of various humancancers. 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. 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 BRAF(WT) patients.
Authors: Kyong Yeun Jung; Sun Wook Cho; Young A Kim; Daein Kim; Byung-Chul Oh; Do Joon Park; Young Joo Park Journal: J Pathol Transl Med Date: 2015-07-15
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