Abstract
BackgroundNKX2.5 is a transcription factor transiently expressed during thyroid organogenesis. Recently, several works have pointed out the oncogenic role of NKX2.5 in a variety of tumors. We therefore hypothesized that NKX2.5 could also play a role in thyroid cancer.MethodsThe validation of NKX2.5 expression was assessed by immunohistochemistry analysis in a Brazilian case series of 10 papillary thyroid carcinoma (PTC) patients. Then, the long-term prognostic value of NKX2.5 and its correlation with clinicopathologic features of 51 PTC patients was evaluated in a cohort with 10-years follow-up (1990–1999). Besides, the effect of NKX2.5 overexpression on thyroid differentiation markers and function was also investigated in a non-tumor thyroid cell line (PCCL3).ResultsNKX2.5 was shown to be expressed in most PTC samples (8/10, case series; 27/51, cohort). Patients who had tumors expressing NKX2.5 showed lower rates of persistence/recurrence (p = 0.013). Overexpression of NKX2.5 in PCCL3 cells led to: 1) downregulation of thyroid differentiation markers (thyrotropin receptor, thyroperoxidase and sodium-iodide symporter); 2) reduced iodide uptake; 3) increased extracellular H2O2 generation, dual oxidase 1 mRNA levels and activity of DuOx1 promoter.ConclusionsIn summary, NKX2.5 is expressed in most PTC samples analyzed and its presence correlates to better prognosis of PTC. In vitro, NKX2.5 overexpression reduces the expression of thyroid differentiation markers and increases ROS production. Thus, our data suggests that NKX2.5 could play a role in thyroid carcinogenesis.
Highlights
NKX2.5 is a transcription factor transiently expressed during thyroid organogenesis
NKX2.5 is expressed in papillary thyroid carcinoma (PTC) samples As expected, NKX2.5 was shown to be expressed in human heart, both in cytoplasm and nucleus (Fig. 1a and b), but not in negative control heart, what is in accordance to literature data [5]
Even though NKX2.5 was described to be transiently expressed only during thyroid organogenesis, until embryonic day 11.5 in mouse 2, normal human thyroid tissue, adjacent to papillary thyroid carcinoma, showed a marked nuclear staining for this transcription factor (Fig. 1e and f), suggesting that NKX2. 5 might be re-expressed later in life or that the proximity to cancer environment had an impact on the pattern of expression of neighbor cells
Summary
NKX2.5 is a transcription factor transiently expressed during thyroid organogenesis. Several works have pointed out the oncogenic role of NKX2.5 in a variety of tumors. The homeodomain transcription factor NKX2.5 is critical for differentiation and proliferation of the primitive pharyngeal endodermal cells [1], being expressed up to the embryonic day 11.5 in the mouse thyroid primordium [2]. The possible role of NKX2.5 in thyroid cancer remains elusive. In the present work, we aimed at evaluating NKX2.5 expression by immunohistochemistry in 10 PTC samples. To assess NKX2.5 association with clinical prognostic, we have included 51 patients from a
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