Trefoil factor 3 is required for differentiation of thyroid follicular cells and acts as a context-dependent tumor suppressor.

Trefoil factor 3 (TFF3) is overexpressed in a variety of solid epithelial cancers, where it has been shown to promote migration, invasion, proliferation, survival and angiogenesis. On the contrary, in the majority of thyroid tumors, it is downregulated, yet its role in the development of thyroid cancer remains unknown. Here we show that TFF3 exhibits strong cytoplasmic staining of normal thyroid follicular cells and colloid and the staining is increased in hyperfunctioning thyroid nodules, while it is decreased in all thyroid cancers of follicular cell origin. By meta-analysis of gene expression datasets, we found that in the thyroid cancer, conversely to the breast cancer, the expression of TFF3 mRNA was downregulated by estrogen signaling and confirmed this by treating thyroid cancer cells with estradiol. Forced expression of TFF3 in anaplastic thyroid cancer cells resulted in decreased cell proliferation, clonal spheroid formation and entry into the S phase. Furthermore, it induced acquisition of epithelial-like cell morphology and expression of the differentiation markers of thyroid follicular cells and transcription factors implicated in the thyroid morphogenesis and function. Taken together, this study provides the first evidence that TFF3 may act as a tumor suppressor or an oncogene depending on the cellular context.

Survey of autoantibody responses against tumor-associated antigens in thyroid cancer.

BACKGROUND: Autoantibodies against tumor-associated antigens (TAAs) have been shown to serve as highly specific serological biomarkers for the diagnosis of various solid cancers. Although the autoimmunity against thyroid tissue specific antigens has been studied extensively, so far, the autoantibody responses against common TAAs such as cancer-testis antigens (CTAs), mutated or differentiation antigens have not been comprehensively analyzed in patients with thyroid cancer. OBJECTIVE: The current study aims to characterize the frequency of autoantibody responses against common TAAs in patients with thyroid cancer and benign thyroid nodules. METHODS: A phage-displayed antigen microarray comprising 65 TAAs was produced and tested with sera from 53 patients with thyroid cancer, 90 patients with benign thyroid nodules and 96 cancer-free individuals, 100 melanoma, 54 breast cancer and 14 lung cancer patients as controls. RESULTS: A panel of 6 TAAs was identified that preferentially reacted with sera from patients with thyroid cancer. The top ranked antigen in this panel was GAGE1 eliciting autoantibody response in 6% of patients with thyroid cancer but not with benign nodules, whereas no reactivity to other CTAs was detected in the sera from patients with thyroid cancer. CONCLUSIONS: Although six TAAs, including one CTA, showed thyroid cancer-associated reactivity, overall, spontaneous humoral immune responses against TAAs are rare in thyroid cancer and their utility for the development of non-invasive assay for the differential diagnosis of thyroid nodules is limited.