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

Chen Hsin Liao, Chau Ting Yeh, Ya Hui Huang, Sheng Ming Wu, Hsiang Cheng Chi, Ming Chieh Tsai, Chung Ying Tsai, Chia Jung Liao, Yi Hsin Tseng, Yang Hsiang Lin, Cheng Yi Chen, I. Hsiao Chung, Wan Li Cheng, Wei Jan Chen, Kwang Huei Lin

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Abstract

Thyroid hormone (T 3) mediates cellular growth, development, and differentiation by binding to the nuclear thyroid hormone receptor (TR). Recent studies suggest that long-term hypothyroidism is associated with human hepatocellular carcinoma (HCC) independent from other major HCC risk factors. Dickkopf (DKK) 4, a secreted protein, antagonizes the Wnt signal pathway. In this study, we demonstrate that T 3 may play a suppressor role by inducing DKK4 expression in HCC cells at both the messenger RNA (mRNA) and protein levels. DKK4 was down-regulated in 67.5% of HCC cancerous tissues. The decrease in DKK4 levels was accompanied by a concomitant decrease in TR protein levels in the matched cancerous tissues in 31% of tissues compared by immunoblotting with the adjacent noncancerous tissues. Further, TR and DKK4 expression levels were positively correlated in both normal and cancerous specimens by tissue array analysis. In function assays, stable DKK4 transfected into J7 or HepG2 cells decreased cell invasion in vitro. Conversely, knocking down DKK4 restores cell invasiveness. DKK4-expressing J7 clones showed increased degradation of β-catenin, but down-regulation of CD44, cyclin D1, and c-Jun. To investigate the effect of DKK4 and TR on tumor growth in vivo, we established a xenograft of J7 cells in nude mice. J7-DKK4 and J7-TRα1 overexpressing mice, which displayed growth arrest, lower lung colony formation index, and smaller tumor size than in control mice, supporting an inhibitory role of DKK4 in tumor progression. Conclusion: Taken together, these data suggest that the TR/DKK4/Wnt/β-catenin cascade influences the proliferation and migration of hepatoma cells during the metastasis process and support a tumor suppressor role of the TR. (Hepatology 2012)

Original languageEnglish
Pages (from-to)910-920
Number of pages11
JournalHepatology
Volume55
Issue number3
DOIs
Publication statusPublished - Mar 2012
Externally publishedYes

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Thyroid Hormone Receptors
Hepatocellular Carcinoma
Catenins
Neoplasms
Tissue Array Analysis
Wnt Signaling Pathway
Proteins
Cyclin D1
Hep G2 Cells
Gastroenterology
Cytoplasmic and Nuclear Receptors
Growth
Hypothyroidism
Thyroid Hormones
Growth and Development
Immunoblotting
Heterografts
Nude Mice
Cell Movement
Signal Transduction

ASJC Scopus subject areas

  • Hepatology

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Dickkopf 4 positively regulated by the thyroid hormone receptor suppresses cell invasion in human hepatoma cells. / Liao, Chen Hsin; Yeh, Chau Ting; Huang, Ya Hui; Wu, Sheng Ming; Chi, Hsiang Cheng; Tsai, Ming Chieh; Tsai, Chung Ying; Liao, Chia Jung; Tseng, Yi Hsin; Lin, Yang Hsiang; Chen, Cheng Yi; Chung, I. Hsiao; Cheng, Wan Li; Chen, Wei Jan; Lin, Kwang Huei.

In: Hepatology, Vol. 55, No. 3, 03.2012, p. 910-920.

Research output: Contribution to journalArticle

Liao, CH, Yeh, CT, Huang, YH, Wu, SM, Chi, HC, Tsai, MC, Tsai, CY, Liao, CJ, Tseng, YH, Lin, YH, Chen, CY, Chung, IH, Cheng, WL, Chen, WJ & Lin, KH 2012, 'Dickkopf 4 positively regulated by the thyroid hormone receptor suppresses cell invasion in human hepatoma cells', Hepatology, vol. 55, no. 3, pp. 910-920. https://doi.org/10.1002/hep.24740
Liao, Chen Hsin ; Yeh, Chau Ting ; Huang, Ya Hui ; Wu, Sheng Ming ; Chi, Hsiang Cheng ; Tsai, Ming Chieh ; Tsai, Chung Ying ; Liao, Chia Jung ; Tseng, Yi Hsin ; Lin, Yang Hsiang ; Chen, Cheng Yi ; Chung, I. Hsiao ; Cheng, Wan Li ; Chen, Wei Jan ; Lin, Kwang Huei. / Dickkopf 4 positively regulated by the thyroid hormone receptor suppresses cell invasion in human hepatoma cells. In: Hepatology. 2012 ; Vol. 55, No. 3. pp. 910-920.
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AU - Liao, Chen Hsin

AU - Yeh, Chau Ting

AU - Huang, Ya Hui

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AU - Chi, Hsiang Cheng

AU - Tsai, Ming Chieh

AU - Tsai, Chung Ying

AU - Liao, Chia Jung

AU - Tseng, Yi Hsin

AU - Lin, Yang Hsiang

AU - Chen, Cheng Yi

AU - Chung, I. Hsiao

AU - Cheng, Wan Li

AU - Chen, Wei Jan

AU - Lin, Kwang Huei

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N2 - Thyroid hormone (T 3) mediates cellular growth, development, and differentiation by binding to the nuclear thyroid hormone receptor (TR). Recent studies suggest that long-term hypothyroidism is associated with human hepatocellular carcinoma (HCC) independent from other major HCC risk factors. Dickkopf (DKK) 4, a secreted protein, antagonizes the Wnt signal pathway. In this study, we demonstrate that T 3 may play a suppressor role by inducing DKK4 expression in HCC cells at both the messenger RNA (mRNA) and protein levels. DKK4 was down-regulated in 67.5% of HCC cancerous tissues. The decrease in DKK4 levels was accompanied by a concomitant decrease in TR protein levels in the matched cancerous tissues in 31% of tissues compared by immunoblotting with the adjacent noncancerous tissues. Further, TR and DKK4 expression levels were positively correlated in both normal and cancerous specimens by tissue array analysis. In function assays, stable DKK4 transfected into J7 or HepG2 cells decreased cell invasion in vitro. Conversely, knocking down DKK4 restores cell invasiveness. DKK4-expressing J7 clones showed increased degradation of β-catenin, but down-regulation of CD44, cyclin D1, and c-Jun. To investigate the effect of DKK4 and TR on tumor growth in vivo, we established a xenograft of J7 cells in nude mice. J7-DKK4 and J7-TRα1 overexpressing mice, which displayed growth arrest, lower lung colony formation index, and smaller tumor size than in control mice, supporting an inhibitory role of DKK4 in tumor progression. Conclusion: Taken together, these data suggest that the TR/DKK4/Wnt/β-catenin cascade influences the proliferation and migration of hepatoma cells during the metastasis process and support a tumor suppressor role of the TR. (Hepatology 2012)

AB - Thyroid hormone (T 3) mediates cellular growth, development, and differentiation by binding to the nuclear thyroid hormone receptor (TR). Recent studies suggest that long-term hypothyroidism is associated with human hepatocellular carcinoma (HCC) independent from other major HCC risk factors. Dickkopf (DKK) 4, a secreted protein, antagonizes the Wnt signal pathway. In this study, we demonstrate that T 3 may play a suppressor role by inducing DKK4 expression in HCC cells at both the messenger RNA (mRNA) and protein levels. DKK4 was down-regulated in 67.5% of HCC cancerous tissues. The decrease in DKK4 levels was accompanied by a concomitant decrease in TR protein levels in the matched cancerous tissues in 31% of tissues compared by immunoblotting with the adjacent noncancerous tissues. Further, TR and DKK4 expression levels were positively correlated in both normal and cancerous specimens by tissue array analysis. In function assays, stable DKK4 transfected into J7 or HepG2 cells decreased cell invasion in vitro. Conversely, knocking down DKK4 restores cell invasiveness. DKK4-expressing J7 clones showed increased degradation of β-catenin, but down-regulation of CD44, cyclin D1, and c-Jun. To investigate the effect of DKK4 and TR on tumor growth in vivo, we established a xenograft of J7 cells in nude mice. J7-DKK4 and J7-TRα1 overexpressing mice, which displayed growth arrest, lower lung colony formation index, and smaller tumor size than in control mice, supporting an inhibitory role of DKK4 in tumor progression. Conclusion: Taken together, these data suggest that the TR/DKK4/Wnt/β-catenin cascade influences the proliferation and migration of hepatoma cells during the metastasis process and support a tumor suppressor role of the TR. (Hepatology 2012)

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