Negative Regulation Mechanism of Pituitary Tumor Transforming Gene 1 (PTTG1) by Thyroid Hormone and Its Physiological Significance

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Pituitary tumor transforming gene 1 (PTTG1) is a novel oncogene that is expressed in most tumors including in human liver cancer. Over-expression of PTTG1 induces cellular transformation and promotes tumor development in animal models. However, the regulation and pathogenic implications of the PTTG1 in hepatocellular carcinoma are largely unknown. Our hypothesis is thyroid hormone (T3) receptor (TR) may be down-regulated in human hepatocellular carcinoma (HCC) to induce PTTG1 over-expression. Additionally, to study the downstream regulation mechanism after thyroid hormone T3 treatment in a TRα1 -overexpressing hepatoma cell line (HepG2-TRα1), oligo-microarray was performed. PTTG1 was down-regulated by T3. The result indicates that PTTG1 may play an important role in hepatocarcinogenesis. We postulate that TR may play a tumor suppressor role during hepato-carcinongenesis. The PTTG1 is a multifunctional gene encoding a 28 kDa, 202 amino-acid protein that induces cell transformation in NIH3T3 cells and tumor formation in nude mice. Further, PTTG1 is involved in liver regeneration and is over-expressed in the hepatoma cell lines. However, PTTG1 regulation by T3 has not been fully characterized, and its pathogenic implications in hepatomas are largely unknown. This study therefore examined the transcriptional regulation of the PTTG1 gene by TR and its physiological significance. The specific aims of this study will be (A) to investigate the regulation mechanism of PTTG1 by T3/TR; (B) functional consequence of PTTG1 down-regulated by T3; (C) to determine whether the T3 regulation can be recapitulated in animal model. Notably, Immunoblot analysis revealed that the PTTG1 was repressed about 76% in HepG2-TRα1 cell at protein level after 72 hr T3 treatment and 79% repression at mRNA level after 72 hr T3 treatment. Additionally, to localize the potential regulatory region in the PTTG1 promoter, we will construct serial deletion of PTTG1 promoter fragment in pA3TK-luc reporter plasmid. The promoter activity will be assayed. Furthermore, we will over-express the PTTG1 gene (gain of function) either by stable transfection or by retroviral approach. Alternatively, the PTTG1 gene will be knock-down by shRNA (loss of function). Finally, the expression of PTTG1 or TR gene in human HCC specimens will be determined to correlate their “inverse” relationship. The possible role of T3/TR in PTTG1 expression will be determined.

Project IDs

Project ID:PC9801-2480
External Project ID:NSC97-2320-B182-025-MY3
StatusFinished
Effective start/end date01/08/0931/07/10

Keywords

  • Oncogene
  • thyroid hormone receptor
  • hepatoma

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