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

Abstract

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.

Forced Trefoil Factor Family Peptide 3 (TFF3) Expression Reduces Growth, Viability, and Tumorigenicity of Human Retinoblastoma Cell Lines

“…[ 5 ]). By contrast, a recent study demonstrated that TFF3 is downregulated in most thyroid tumors [ 31 ]. Along this line our study revealed, that compared to the healthy human retina TFF3 mRNA (data not shown) and TFF3 protein expression levels are likewise below detection levels in primary retinoblastoma samples ( S2 Fig ).…”

“…In human corneal epithelia cells, proliferation likewise decreased 24 h after stimulation with recombinant TFF3 [ 42 ]. Along this line, forced expression of TFF3 significantly reduced proliferation of anaplastic thyroid cancer cells [ 31 ]. By contrast, Sun et al (2014) demonstrated that TFF3 promotes proliferation of gastric mucosal epithelial cells [ 43 ] and most recent studies likewise reported that rTFF3 enhanced the proliferation of gastric endothelial and human corneal epithelial cells [ 44 ; 45 ].…”

“…Alternatively, these contradictory data again can be explained in terms of cell-specific actions: in mammary carcinoma and prostate cancer cells forced expression of TFF3 significantly increased cell proliferation, viability and survival [ 38 ; 46 ], whereas it triggered a strong pro-apoptotic and anti-proliferative effect in retinoblastoma cell lines investigated in our study. An anti-proliferative effect of forced TFF3 expression has also been observed in anaplastic thyroid cancer cells in a recent study by Abols et al (2015) and the authors suggested that TFF3 may act as a tumor suppressor or an oncogene depending on the cellular context [ 31 ].…”

Comprehensive Evaluation of TFF3 Promoter Hypomethylation and Molecular Biomarker Potential for Prostate Cancer Diagnosis and Prognosis

“…In relation to cancer, TFF3 has been proposed to function both as an oncogene and as a tumor suppressor. Thus, high TFF3 expression has been associated with favorable prognosis in ovarian cancer [ 22 ] and with low grade in early stage breast cancer [ 23 ], and TFF3 seems to act as a tumor suppressor in thyroid cancer [ 24 ]. In contrast, TFF3 protein overexpression has been linked with aggressive disease in colon, gastric, and mammary cancer [ 25 , 26 , 27 , 28 ].…”

A molecular view of the normal human thyroid structure and function reconstructed from its reference transcriptome map

“…Recently TFF3 has been described as a gene that could function as an oncogene or oncosuppressor in dependence on the cellular context. In fact, in many types of solid tumors an increase of TFF3 expression level was observed, while in all thyroid cancers of follicular cell origin its expression was decreased when in normal thyroid it was highly expressed [31]. Other known overexpressed genes on chr21 are CSTB (cystatin B) and SOD1 (superoxide dismutase 1, soluble) (Table 2) encoding, respectively, for a protease inhibitor that has been reported to protect neurons from oxidative stress and for a free superoxide radical destroyer that controls the redox state of the cells.…”