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
External Project ID:NSC97-2320-B182-025-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/09 → 31/07/10 |
Keywords
- Oncogene
- thyroid hormone receptor
- hepatoma
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