The Role of PPAR gamma in thyroid cancer

Summary

Differentiation therapy for thyroid cancer by targeting the fusion gene PAX8-PPARgamma.

Supervisor(s)

Dr Roderick Clifton-Bligh

Research Location

North Shore - Kolling Institute of Medical Research

Program Type

Masters/PHD

Synopsis

Our laboratory has studied a subtype of thyroid cancer in which a chromosomal translocation fuses the thyroid specific transcription factor PAX8 with the nuclear receptor PPARg gene. The resulting fusion protein PAX8-PPARg has mixed transcriptional function that mimics in part the functions of its separate partners. In particular, the fusion protein is a strong transcriptional activator of the sodium-iodide symporter (NIS gene) which is a key target in routine thyroid cancer treatment by means of radioactive iodine administration. However, for reasons yet unclear this key gene is downregulated in many thyroid cancers. We have recently made additional observations that strongly suggest that the MAP kinase pathway is activated in PAX8-PPAR_-containing thyroid cancers, as it commonly is in other thyroid cancer subtypes. This observation may explain low NIS levels, since MAP kinase activation is known to inhibit NIS expression. PAX8-PPAR_-containing follicular thyroid tumours provide a unique perspective on the role of PPAR_ in cancer. Defining related signalling pathways is at the forefront of cancer research, since inhibitors of key targets have now been successfully translated into clinical practice. The principal hypotheses of this project are: (1) that the PAX8-PPARg oncogene causes cancer because it acts in concert with activation of tyrosine kinase-MAP kinase signalling; and (2) that thyroid cancer cells expressing PAX8-PPARg will be susceptible to the combined action of PPARg agonists and kinase inhibitors, with particular relevance to enhanced expression of the sodium-iodide symporter that renders thyroid cells susceptible to radioactive iodine ablation.

Additional Information

Techniques used in this project: cell culture, reporter gene studies, protein analysis, siRNA knock-down studies.

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Keywords

Thyroid cancer, cancer biology, cancer therapy., Cancer, Endocrinology, gene regulation, Cancer chemotherapy., Cancer & leukaemia, Liver & hormonal disorders, Cell biology, Genes in biology & medicine

Opportunity ID

The opportunity ID for this research opportunity is: 206