Abstract |
Inactivation and silencing of PTEN have been observed in multiple cancers, including follicular thyroid carcinoma. PTEN (phosphatase and tensin homologue deleted from chromosome 10) functions as a tumour suppressor by opposing the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) signalling pathway. Despite correlative data, how deregulated PTEN signalling leads to thyroid carcinogenesis is not known. Mice harbouring a dominant-negative mutant thyroid hormone receptor beta (TRbeta(PV/PV) mice) spontaneously develop follicular thyroid carcinoma and distant metastases similar to human cancer. To elucidate the role of PTEN in thyroid carcinogenesis, we generated TRbeta(PV/PV) mice haploinsufficient for Pten (TRbeta(PV/PV)Pten(+/-) mouse). PTEN deficiency accelerated the progression of thyroid tumour and increased the occurrence of metastasis spread to the lung in TRbeta(PV/PV)Pten(+/-) mice, thereby significantly reducing their survival as compared with TRbeta(PV/PV)Pten(+/+) mice. AKT activation was further increased by two-fold in TRbeta(PV/PV)Pten(+/-) mice thyroids, leading to increased activity of the downstream mammalian target of rapamycin (mTOR)-p70S6K signalling and decreased activity of the forkhead family member FOXO3a. Consistently, cyclin D1 expression was increased. Apoptosis was decreased as indicated by increased expression of nuclear factor-kappaB ( NF-kappaB) and decreased caspase-3 activity in the thyroids of TRbeta(PV/PV)Pten(+/-) mice. Our results indicate that PTEN deficiency resulted in increased cell proliferation and survival in the thyroids of TRbeta(PV/PV)Pten(+/-) mice. Altogether, our study provides direct evidence to indicate that in vivo, PTEN is a critical regulator in the follicular thyroid cancer progression and invasiveness.
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Authors | C J Guigon, L Zhao, M C Willingham, S-Y Cheng |
Journal | Oncogene
(Oncogene)
Vol. 28
Issue 4
Pg. 509-17
(Jan 29 2009)
ISSN: 1476-5594 [Electronic] England |
PMID | 18997818
(Publication Type: Journal Article, Research Support, N.I.H., Intramural)
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Chemical References |
- Carrier Proteins
- Ccnd1 protein, mouse
- Forkhead Box Protein O3
- Forkhead Transcription Factors
- FoxO3 protein, mouse
- NF-kappa B
- Thyroid Hormone Receptors beta
- Cyclin D1
- Phosphotransferases (Alcohol Group Acceptor)
- MTOR protein, human
- mTOR protein, mouse
- Proto-Oncogene Proteins c-akt
- Ribosomal Protein S6 Kinases, 70-kDa
- TOR Serine-Threonine Kinases
- PTEN Phosphohydrolase
- Pten protein, mouse
- Casp3 protein, mouse
- Caspase 3
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Topics |
- Animals
- Apoptosis
(genetics)
- Carrier Proteins
(genetics, metabolism)
- Caspase 3
(genetics, metabolism)
- Cell Proliferation
- Cell Survival
(genetics)
- Chromosomes, Mammalian
(genetics, metabolism)
- Cyclin D1
(genetics, metabolism)
- Disease Models, Animal
- Enzyme Activation
(genetics)
- Forkhead Box Protein O3
- Forkhead Transcription Factors
(genetics, metabolism)
- Lung Neoplasms
(genetics, metabolism, pathology, secondary)
- Mice
- Mice, Mutant Strains
- Mice, Transgenic
- NF-kappa B
(genetics, metabolism)
- Neoplasm Invasiveness
- Neoplasm Metastasis
- PTEN Phosphohydrolase
(genetics, metabolism)
- Phosphatidylinositol 3-Kinases
(genetics, metabolism)
- Phosphotransferases (Alcohol Group Acceptor)
(genetics, metabolism)
- Proto-Oncogene Proteins c-akt
(genetics, metabolism)
- Ribosomal Protein S6 Kinases, 70-kDa
(genetics, metabolism)
- Signal Transduction
(genetics)
- TOR Serine-Threonine Kinases
- Thyroid Hormone Receptors beta
(genetics, metabolism)
- Thyroid Neoplasms
(genetics, metabolism, pathology)
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