Dickkopf 4 positively regulated by thyroid hormone receptor suppresses cell invasion in human hepatoma cells

• Main Authors: Chen Hsin Liao, 廖辰芯
• Other Authors: K. H. Lin
• Format: Others
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/87664543925676905353

博士 === 長庚大學 === 生物醫學研究所 === 97 === The thyroid hormone, 3, 3', 5-triiodo-L-thyronine (T3) mediate cellular growth, development and differentiation by binding to nuclear thyroid hormone receptor to regulate target genes transcriptional activities. In previous study, we have carried out cDNA microarray to identify genes regulated by T3, the results indicate that Dickkopf 4 (DKK4) is up-regulated by T3. DKK4, a secreted protein, participates in Wnt signal pathway and plays an inhibition role via binding to Wnt/FZ co-receptor LRP5/6 to suppress Wnt signal. The expression metastasis related proteins such as c-Myc, CD44, fibronectin and uPAR….ect was also down-regulated. All those genes play critical roles in aberrant cellular proliferation and carcinogenesis. In this study, we demonstrate that the induction of DKK4 protein expression according to T3 in TR1 over-expressing cell at the mRNA and protein levels. Similar observation was made on the regulation of DKK4 by using on rats which received surgical thyroidectomies (TX) as an in vivo model. Also, DKK4 is abundantly expressed in noncancerous liver tissues and downregulated in cancerous tissues. Function assays with stable DKK4 transfecting in J7 and SK-Hep-1 revealed that DKK4 expression decreased cell growth, migration and invasion. DKK4 reduced cytoplasmic accumulation of -catenin. Further, downregulation of c-Myc, fibronectin and CD44 was found in the DKK4 expressing clones supporting an inhibitory role of DKK4 in tumor progression. Therefore, we conclude that TRs/DKK4/Wnt-catenin cascade influences the proliferation and migration of hepatoma cells during the metastasis process. Finally, we establish that thyroid hormone receptor may play a tumor suppressor role.