Abstract
Although accumulating evidence has confirmed the important roles of thyroid hormone (T3) 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 T3 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 T3 were apoptosis resistant, even when TRAIL was upregulated. This apoptotic resistance may be attributable to simultaneous upregulation of Bcl-xL by T3, because (1) knockdown of T3-induced Bcl-xL expression suppressed T3-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, T3-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.
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Abbreviations
- T3:
-
thyroid hormone
- TRs:
-
thyroid hormone receptors
- TRE:
-
thyroid response element
- TRAIL:
-
TNF-related apoptosis-inducing ligand
- HCC:
-
hepatocellular carcinoma
- ActD:
-
actinomycin D
- CHX:
-
cycloheximide
- (r)-TRAIL:
-
recombinant TRAIL
- Ad-TRAIL:
-
Adenovirus expressing TRAIL
- NF-κB:
-
nuclear factor kappa B
- cFLIP:
-
cellular FLICE-like inhibitory protein
- MAPK:
-
mitogen-activated protein kinase
- PKC:
-
protein kinase C
- MMP:
-
matrix metalloproteinase
- SCID:
-
severe combined immunodeficiency
- H&E:
-
hematoxylin and eosin
- IHC:
-
immunohistochemical staining
- ChIP:
-
chromatin immunoprecipitation
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Acknowledgements
This work was supported by grants from Chang-Gung University, Taoyuan, Taiwan (CMRPD 34013, NMRP 140511) and National Science Council of the Republic of China (NSC 94–2320-B-182–052).
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Chi, HC., Chen, SL., Liao, CJ. et al. Thyroid hormone receptors promote metastasis of human hepatoma cells via regulation of TRAIL. Cell Death Differ 19, 1802–1814 (2012). https://doi.org/10.1038/cdd.2012.58
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DOI: https://doi.org/10.1038/cdd.2012.58
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