Abstract
PAX8 is a transcription factor essential for thyroid gland development, as well as for the maintenance of the thyroid differentiated state in the adult. In particular, PAX8 has been comprehensively shown to regulate genes that are considered markers of thyroid differentiation. However, a better knowledge of genes transcriptionally regulated by PAX8 is desirable to clarify its role in endocrine syndromes and cancer susceptibility. In order to further investigate PAX8 downstream targets, we recently performed a genome-wide expression analysis following PAX8 knockdown in FRTL-5 thyroid cells and Neuropilin-2 was identified as a potential transcriptional target of PAX8. In this study, we determined the role of the transcription factor PAX8 in the regulation of Neuropilin-2 expression. Indeed, in thyroid cells PAX8 directly binds the Neuropilin-2 promoter leading to its transcriptional repression. Interestingly, we observed an inverse correlation between the expression of PAX8 and Neuropilin-2 in thyroid carcinoma tissues and cell lines compared to non-tumor counterparts, suggesting a critical role of PAX8 in regulating Neuropilin-2 expression in vivo. Notably, ectopic overexpression of PAX8 in FB-2 thyroid cancer cells promotes Neuropilin-2 downregulation producing a significant reduction in cell proliferation, migration ability, and invasion activity and reverting the cell phenotype from mesenchymal to a more epithelial one. These findings uncover the novel interplay between PAX8 and Neuropilin-2, which is likely to be important in the pathogenesis of thyroid diseases.
Highlights
Neuropilins (NRP1 and NRP2) are multifunctional single-spanning trans-membrane glycoproteins that play a central role in neuronal and blood vessel development as receptors for members of the class-3 semaphorin family (SEMAs) of axonal guidance factors and for members of the vascular endothelial growth factor (VEGF) family of angiogenesis stimulators [1,2,3,4,5]
We searched for PAX8 binding sites in a region of about 2000 bp of NRP2 5’-flanking region and the analysis showed the presence of PAX8 consensus sequences in the genomic region analyzed
We show that the PAX8 antibody is able to immunoprecipitate the chromatin containing the NRP2 promoter
Summary
Neuropilins (NRP1 and NRP2) are multifunctional single-spanning trans-membrane glycoproteins that play a central role in neuronal and blood vessel development as receptors for members of the class-3 semaphorin family (SEMAs) of axonal guidance factors and for members of the vascular endothelial growth factor (VEGF) family of angiogenesis stimulators [1,2,3,4,5]. NRP2 promotes tumor growth and metastasis in pancreatic adenocarcinoma and colorectal cancer models [27, 28]. NRP2 is known as a coreceptor for vascular endothelial growth factor (VEGF)-D, which is a well-known lymphangiogenic factor that plays an important role in lymph node metastasis of various human cancers, including papillary thyroid carcinoma (PTC) [37, 38]
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