Abstract
PAX8 is a thyroid-specific transcription factor whose expression is dysregulated in thyroid cancer. A recent study using a conditional knock-out mouse model identified 58 putative PAX8 target genes. In the present study, we evaluated the expression of 11 of these genes in normal and tumoral thyroid tissues from patients with papillary thyroid cancer (PTC). ATP1B1, GPC3, KCNIP3, and PRLR transcript levels in tumor tissues were significantly lower in PTCs than in NT, whereas LCN2, LGALS1 and SCD1 expression was upregulated in PTC compared with NT. Principal component analysis of the expression of the most markedly dysregulated PAX8 target genes was able to discriminate between PTC and NT. Immunohistochemistry was used to assess levels of proteins encoded by the two most dyregulated PAX8 target genes, LCN2 and GPC3. Interestingly, GPC3 was detectable in all of the NT samples but none of the PTC samples. Collectively, these findings point to significant PTC-associated dysregulation of several PAX8 target genes, supporting the notion that PAX8-regulated molecular cascades play important roles during thyroid tumorigenesis.
Highlights
Tissue-specific transcription factors are critical for the development and function of the thyroid gland
To gain further insight into the roles played by PAX8 target genes during thyroid tumorigenesis, we investigated their expression in a cohort of papillary thyroid cancer (PTC) with well characterized clinicobiological features
We evaluated the expression in normal thyroid tissue (NT) and PTC of 11 of these genes with established roles in thyroid cell function or in cancerogenesis, which displayed marked dysregulation in the Pax8 knock-out mice [8]
Summary
Tissue-specific transcription factors are critical for the development and function of the thyroid gland. Several thyroid-specific transcription factors have been identified, including TTF-1 (NKX2-1), TTF-2 (FOXE1), PAX8, and HEX, and numerous roles have been described for each [1]. Its critical contribution during thyroid development was first highlighted by Mansouri and coworkers, who demonstrated the absence of thyroid follicular cell formation in Pax knock-out mice [4]. Most cases of human congenital hypothyroidism due to thyroid dysgenesis are caused by heterozygous loss-of-function mutations involving PAX8 [5]. PAX8 appears to control the expression of various genes that play key roles in the function of thyroid follicular cells, including those encoding thyroglobulin (TG), thyroperoxidase (TPO), and the sodium-iodide symporter
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