Thyroid hormone receptors promote metastasis of human hepatoma cells via regulation of TRAIL

Although accumulating evidence has confirmed the important roles of thyroid hormone (T 3 ) and its receptors (TRs) in tumor progression, the specific functions of TRs in carcinogenesis remain unclear. In the present study, tumor necrosis factor (TNF)-related apoptosis-inducing ligand ( TRAIL ) was d...

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Veröffentlicht in:Cell death and differentiation 2012-11, Vol.19 (11), p.1802-1814
Hauptverfasser: Chi, H-C, Chen, S-L, Liao, C-J, Liao, C-H, Tsai, M-M, Lin, Y-H, Huang, Y-H, Yeh, C-T, Wu, S-M, Tseng, Y-H, Chen, C-Y, Tsai, C-Y, Chung, I-H, Chen, W-J, Lin, K-H
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Sprache:eng
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Zusammenfassung:Although accumulating evidence has confirmed the important roles of thyroid hormone (T 3 ) and its receptors (TRs) in tumor progression, the specific functions of TRs in carcinogenesis remain unclear. In the present study, tumor necrosis factor (TNF)-related apoptosis-inducing ligand ( TRAIL ) was directly upregulated by T 3 in TR-overexpressing hepatoma cell lines. TRAIL is an apoptotic inducer, but it can nonetheless trigger non-apoptotic signals favoring tumorigenesis in apoptosis-resistant cancer cells. We found that TR-overexpressing hepatoma cells treated with T 3 were apoptosis resistant, even when TRAIL was upregulated. This apoptotic resistance may be attributable to simultaneous upregulation of Bcl-xL by T 3 , because (1) knockdown of T 3 -induced Bcl-xL expression suppressed T 3 -mediated protection against apoptosis, and (2) overexpression of Bcl-xL further protected hepatoma cells from TRAIL-induced apoptotic death, consequently leading to TRAIL-promoted metastasis of hepatoma cells. Moreover, T 3 -enhanced metastasis in vivo was repressed by the treatment of TRAIL-blocking antibody. Notably, TRAIL was highly expressed in a subset of hepatocellular carcinoma (HCC) patients, and this high-level expression was significantly correlated with that of TRs in these HCC tissues. Together, our findings provide evidence for the existence of a novel mechanistic link between increased TR and TRAIL levels in HCC. Thus, TRs induce TRAIL expression, and TRAIL thus synthesized acts in concert with simultaneously synthesized Bcl-xL to promote metastasis, but not apoptosis.
ISSN:1350-9047
1476-5403
DOI:10.1038/cdd.2012.58