S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Medicine (의학과) Theses (Ph.D. / Sc.D._의학과)
Pathogenetic role of Wnt signaling pathway and the function of Dickkopf-1 in thyroid cancers
- 의과대학 의학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의학과 분자유전체의학 전공, 2013. 2. 박영주.
- Wnt/beta-catenin signaling plays a role in tumorigenesis of human papillary thyroid cancer (PTC). Dickkopf (Dkk) -1 is a known inhibitor of Wnt/beta-catenin signaling, the therapeutic potential of which is undetermined. In this study, we investigated the therapeutic potential of Dkk-1 in human PTC.
In order to evaluate the clinical significance of Wnt/beta-catenin pathway, we investigated the expression of Wnt in relation to downstream molecules including beta-catenin, cyclin D1, E-cadherin in papillary thyroid cancer. In addition we investigated the anti-tumoral effect of Dkk-1 on two different PTC cell lines, in vitro, to determine the therapeutic potential of Dkk-1 in PTC.
A paired comparison between human PTC and normal thyroid tissues from PTC patients revealed that Wnt3 gene expression and total beta-catenin proteins were up-regulated in human PTC tissues. Tissue microarray data revealed that 9.5% of PTC and 100.0% of anaplastic thyroid cancer had aberrant cytoplasmic staining of beta-catenin, while membranous staining was found in all normal tissue. Aberrant locations of beta-catenin in PTC tissues were correlated with the loss of membranous E-cadherin expression. Dkk-1 treatment inhibited PTC cell survival via a pro-apoptotic action. Dkk-1 reversed the aberrant expression of beta-catenin from nucleus to membrane and inhibited basal levels of TCF/LEF dependent transcriptional activities. Furthermore, Dkk-1 inhibited cell viability in dose dependent manners and adenoviral transduction of constitutively active beta-catenin blocked these effects, suggesting that an anti-tumoral effect of Dkk-1 is mediated by Wnt/beta-catenin signaling. In addition, Dkk-1 also recovered the loss of membranous E-cadherin expression with consequent inhibition of cell migration and invasion in both cell lines.
Our results suggest that Dkk-1 inhibited human PTC survival and migration by regulating Wnt/beta-catenin signaling and E-cadherin expression. Thus, the interruption of this signaling may therapeutically be useful in thyroid cancer.