Endocrine Abstracts

Reduced expression or activity of the thyroid hormone receptors (TRs) are common events in cancer, suggesting that these receptors could act as tumor suppressors. We have previously shown that TRβ expression in SK-hep1 hepatocarcinoma cells (SK-TRβ cells), reduces tumor growth and strikingly inhibits invasion, extravasation, and metastasis formation in nude mice. These effects could be related to a decreased expression in these cells of prometastatic genes, such as COX2, MMP9 or ID1. We have now found that transcripts for these genes are also decreased in tumors and metastasis originated by SK-TRβ cells in nude mice. Using transient transfection assays, we have localized CRE, AP1 and SP1 sites in their promoters that appear to mediate the inhibitory effect of TRβ. This suggests that cross-talk with other transcription factors plays an important role in the repression of prometastatic gene transcription by the receptor. One mechanism that could explain suppression of prometastatic gene expression by TRβ is the recruitment of corepressor complexes. Indeed, we found that expression of the corepressor NcoR is significantly higher in SK-TRβ cells than in parental cells and is also increased in tumors and metastasis. NcoR silencing with interference RNA produces a strong increase in transcript levels of several prometastatic genes and enhances cellular invasion in matrigel assays. These effects appear to be specific for NCoR, since depletion of the corepressor SMRT is ineffective. Furthermore, NCoR silencing reverses significantly the effect of TRβ expression, enhancing tumor growth and invasion, extravasation and metastasis development when cells are inoculated into nude mice. These changes are associated with increased expression of prometastatic genes in the tumors and in the metastatic injuries.

These results demonstrate the essential role of the corepressor NcoR in the tumor suppressive actions of TRβ, and suggest the importance of the corepressor as a potential therapeutic target in cancer.