Pituitary tumor transforming gene 1 (PTTG1) is expressed in most tumors. However, whether thyroid hormone (T3) and its receptors (TRs) regulate PTTG1 in human hepatocellular carcinomas (HCC) remains unclear. Previous cDNA microarrays revealed PTTG1 is down-regulated by T3/TR. This study investigated the significance of PTTG1 regulation by T3 in HCC cells. The PTTG1 mRNA and protein expression were repressed by T3 in HepG2-TR cells over-expressing TR. Similar results were observed in thyroidectomized rats. To localize the regulatory region in the PTTG1 promoter, serial deletions of mutant PTTG1 promoters were constructed. The promoter activity of the PTTG1 gene was repressed (2551%) by T3. Additionally, these findings indicate that PTTG1 may be regulated by Sp1 transcription factor. The critical role of −594 and −520 Sp1 binding sites was confirmed by electrophoretic mobility shift assay (EMSA). Transfection with Sp1 expression vector enhanced PTTG1 promoter fragment reporter activity. Also, Sp1 was down-regulated in HepG2-TRα1 cells and in thyroidectomized rat models following T3 treatment. Additionally, ectopic expression of PTTG1 promotes cell proliferation in Hep3B hepatoma cells. Conversely, knock-down of PTTG1 or Sp1 expression reduces cell proliferation in HepG2 cells. Also, TR expression was reduced in HCC over-expressing PTTG1. Together, these findings indicate that PTTG1 gene expression is mediated by Sp1 and is indirectly down-regulated by T3. Finally, over-expression of PTTG1 or SP1 in HCCs is TR-dependant and crucial in the development of HCC.
03 - 07 May 2008
European Society of Endocrinology