SUN-338 Inflammation Promotes Aggressive Thyroid Cancer Progression in a Mouse Model

Thyroid cancer is the most common endocrine malignancy. The association between inflammation and thyroid cancer has long been recognized. However, a cause-effect relationship at the molecular level has yet to be elucidated. We have created a mutant mouse, which expresses a dominant negative thyroid hormone receptor β (denoted as TRβPV) and deficiency in one allele of the Pten gene (Thrb(PV/PV)Pten(+/-) mice). This mutant mouse exhibits aggressive follicular thyroid cancer similarly as in patients. We explored how inflammation could contribute to thyroid carcinogenesis in Thrb(PV/PV)Pten(+/-) mice. Using FACS analysis, we found significantly increased inflammatory monocytes in thyroid tumors of Thrb(PV/PV)Pten(+/-) mice. We next identified alterations in inflammation-related genes during thyroid carcinogenesis by cDNA microarrays to compare global gene expression profiles between thyroids of wild-type and Thrb(PV/PV)Pten(+/-) mice. Gene array data revealed that a total 2,410 genes were differentially altered in thyroid tumors of Thrb(PV/PV)Pten(+/-) mice (1,097 genes were up-regulated, and 1,313 genes were down-regulated). Analysis of the expression data showed an enrichment of genes that were associated with immune cell markers, cytokines, and chemokines, including Ptgs1, Sphk1, OPN, Tnfrsf18, CCL12, and IL6. Using Q/PCR, we validated the array data to show the significant increase in the expression of pro-inflammatory target genes [such as Ptgs1 (3 folds); Sphk1 (7.5 folds); OPN (5.4 folds), MCP1 (2.5 folds), IL17 (10.3 folds) and Tnfrsf18 (9.4 folds)] and significant decrease in the expression of anti-inflammatory genes [Ephx2 (2.3 folds) and CD163 (5.9 folds)] in thyroid tumors of Thrb(PV/PV)Pten(+/-) mice. We further delineated the inflammatory role of osteopontin (OPN) in the thyroid carcinogenesis of Thrb(PV/PV)Pten(+/-) mice. OPN is thought to facilitate the recruitment of monocytes/macrophages and to mediate cytokine secretion in leukocytes. Extracellular OPN functions through its interaction with multiple cell surface receptors (e.g., integrins and CD44), leading to the activation of PI3K-AKT and NF-kB signaling. We found that the protein abundance of OPN and integrin β1 was highly increased and concordantly, the downstream effectors, AKT and NF-kB were significantly elevated to drive thyroid tumor progression of Thrb(PV/PV)Pten(+/-) mice. These results demonstrated that increased inflammation driven by elevated expression of immune-related genes and cytokines promoted thyroid cancer progression and that OPN played important roles in thyroid carcinogenesis. These preclinical findings suggest that OPN can be a potential target for thyroid cancer therapy.