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Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment.

ABSTRACT: Pituitary tumor transforming gene (PTTG)-binding factor (PBF or PTTG1IP) is a little characterized proto-oncogene that has been implicated in the etiology of breast and thyroid tumors. In this study, we created a murine transgenic model to target PBF expression to the thyroid gland (PBF-Tg mice) and found that these mice exhibited normal thyroid function, but a striking enlargement of the thyroid gland associated with hyperplastic and macrofollicular lesions. Expression of the sodium iodide symporter (NIS), a gene essential to the radioiodine ablation of thyroid hyperplasia, neoplasia, and metastasis, was also potently inhibited in PBF-Tg mice. Critically, iodide uptake was repressed in primary thyroid cultures from PBF-Tg mice, which could be rescued by PBF depletion. PBF-Tg thyroids exhibited upregulation of Akt and the TSH receptor (TSHR), each known regulators of thyrocyte proliferation, along with upregulation of the downstream proliferative marker cyclin D1. We extended and confirmed findings from the mouse model by examining PBF expression in human multinodular goiters (MNG), a hyperproliferative thyroid disorder, where PBF and TSHR was strongly upregulated relative to normal thyroid tissue. Furthermore, we showed that depleting PBF in human primary thyrocytes was sufficient to increase radioiodine uptake. Together, our findings indicate that overexpression of PBF causes thyroid cell proliferation, macrofollicular lesions, and hyperplasia, as well as repression of the critical therapeutic route for radioiodide uptake.

SUBMITTER: Read ML

PROVIDER: S-EPMC3184940 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment.

Read Martin L ML Lewy Greg D GD Fong Jim C W JC Sharma Neil N Seed Robert I RI Smith Vicki E VE Gentilin Erica E Warfield Adrian A Eggo Margaret C MC Knauf Jeffrey A JA Leadbeater Wendy E WE Watkinson John C JC Franklyn Jayne A JA Boelaert Kristien K McCabe Christopher J CJ

Cancer research 20110815 19

Pituitary tumor transforming gene (PTTG)-binding factor (PBF or PTTG1IP) is a little characterized proto-oncogene that has been implicated in the etiology of breast and thyroid tumors. In this study, we created a murine transgenic model to target PBF expression to the thyroid gland (PBF-Tg mice) and found that these mice exhibited normal thyroid function, but a striking enlargement of the thyroid gland associated with hyperplastic and macrofollicular lesions. Expression of the sodium iodide symp ...[more]

PMID: 21844185

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Project description:ObjectiveAn oncogenic protein, pituitary tumor transforming gene 1 binding factor (PTTG1IP, also called PBF), has been found to be expressed in various cancers. However, few studies have explored its prognostic significance and biologic function in epithelial ovarian cancer (EOC).MethodsBased on the Cancer Genome Atlas (TCGA) database, this study determined the differential expression of PBF at the mRNA level in EOC and normal tissues, which was then verified using real-time PCR and western blotting. Moreover, the Kaplan-Meier method and the Cox regression method were adopted to assess the clinical value of PBF in EOC. A nomogram model was constructed to evaluate the prognostic performance of PBF in EOC. Gene set enrichment analysis (GSEA) was employed to evaluate the signaling and pathway enrichment of PBF in EOC. The association between PBF expression and tumor-infiltrating immune cells (TIICs) in EOC was examined by single-sample GSEA and TIMER.ResultsPBF was significantly higher in EOC than normal tissues as shown through TCGA database, and this result was verified by qRT-PCR and western blotting of EOC tissues and different cell lines. High PBF was associated with tumor size and lymphatic metastasis status. Kaplan-Meier (KM) analysis indicated that high PBF expression correlated with poor prognosis in patients with EOC (P < 0.0001). Moreover, multivariate Cox regression analysis was used to verify that PBF is an independent prognostic factor for EOC. The nomogram model exhibited moderate predictive accuracy and clinical utility in predicting EOC prognosis. The GSEA revealed that the expression of signaling pathways, such DNA damage replication, p53 pathway, Akt phosphorylation pathway, and estrogen-dependent nuclear pathway, were increased in the phenotype with high PBF expression. PBF expression was associated with neutrophil cells, iDC cells, NK cells, and Tem cells.ConclusionAs a prognostic biomarker for EOC, PBF was found to be correlated with immune infiltration, and may therefore be a promising target for immunotherapy for EOC.

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Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment.

Publications

Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment.

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