title: Thyroid hormone receptors promote metastasis of human hepatoma cells via regulation of TRAIL.
abstract: 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.
authors.affiliation: Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.
authors.forename: H-C
authors.initials: HC
authors.lastname: Chi
authors.forename: S-L
authors.initials: SL
authors.lastname: Chen
authors.forename: C-J
authors.initials: CJ
authors.lastname: Liao
authors.forename: C-H
authors.initials: CH
authors.lastname: Liao
authors.forename: M-M
authors.initials: MM
authors.lastname: Tsai
authors.forename: Y-H
authors.initials: YH
authors.lastname: Lin
authors.forename: Y-H
authors.initials: YH
authors.lastname: Huang
authors.forename: C-T
authors.initials: CT
authors.lastname: Yeh
authors.forename: S-M
authors.initials: SM
authors.lastname: Wu
authors.forename: Y-H
authors.initials: YH
authors.lastname: Tseng
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chen
authors.forename: C-Y
authors.initials: CY
authors.lastname: Tsai
authors.forename: I-H
authors.initials: IH
authors.lastname: Chung
authors.forename: W-J
authors.initials: WJ
authors.lastname: Chen
authors.forename: K-H
authors.initials: KH
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014284:Triiodothyronine / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D011988:Receptors, Thyroid Hormone; D053221:TNF-Related Apoptosis-Inducing Ligand; D051020:bcl-X Protein; D014284:Triiodothyronine; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9