Overexpression of modified human TRβ1 suppresses the growth of hepatocarcinoma SK-hep1 cells in vitro and in xenograft models

Association studies suggest that TR beta 1 functions as a tumor suppressor. Thyroid hormone receptors (TRs) mediate transcriptional responses through a highly conserved DNA-binding domain (DBD). We previously constructed an artificially modified human TR beta 1 (m-TR beta 1) via the introduction of a 108-bp exon sequence into the corresponding position of the wild-type human TR beta 1 (TR beta 1) DBD. Studies confirmed that m-TR beta 1 was functional and could inhibit the proliferation of breast cancer MDA-MB-468 cells in vitro. To understand the role of m-TR beta 1 in liver tumor development, we adopted a gain-of-function approach by stably expressing TR beta (m-TR beta 1 and TR beta 1) genes in a human hepatocarcinoma cell line, SK-hep1 (without endogenous TR beta), and then evaluated the effects of the expressed TR beta on cancer cell proliferation, migration, and tumor growth in cell-based studies and xenograft models. In the presence of 3,5,3-l-triiodothyronine (T3), the expression of TR beta in SK-hep1 cells inhibited cancer cell proliferation and impeded tumor cell migration through the up-regulation of 4-1BB, Caspase-3, and Bak gene expression; down-regulation of Bcl-2 gene expression; and activation of the Caspase-3 protein. TR beta expression in SK-hep1 led to less tumor growth in xenograft models. Additionally, the anti-tumor effect of m-TR beta 1 was stronger than that of TR beta 1. These data indicate that m-TR beta 1 can act as a tumor suppressor in hepatocarcinoma and its role was significantly better than that of TR beta 1.