MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma. Issue 3 (March 2016)

• Record Type: Journal Article
• Authors: Romitti, Mírian; Wajner, Simone Magagnin; Ceolin, Lucieli; Ferreira, Carla Vaz; Pinto Ribeiro, Rafaela Vanin; Rohenkohl, Helena Cecin; Weber, Shana de Souto; Lopez, Patrícia Luciana da Costa; Fuziwara, Cesar Seigi; Kimura, Edna Teruko; Maia, Ana Luiza
• Is Part Of: Endocrine-related cancer. Volume 23:Issue 3(2016)
• Page Start: 135
• Page End: 146
• Publication Date: 2016-03
• Subjects: type 3 deiodinase, papillary thyroid carcinoma -- MAPK genetic alterations -- Sonic Hedgehog pathway; Endocrine glands -- Cancer -- Periodicals; Endocrinology -- Periodicals; Cancer -- Endocrine aspects -- Periodicals; 616.9944005
• DOI: 10.1530/ERC-15-0162
• Languages: English
• ISSNs: 1351-0088

Abstract

Abstract : Type 3 deiodinase (DIO3, D3) is reactivated in human neoplasias. Increased D3 levels in papillary thyroid carcinoma (PTC) have been associated with tumor size and metastatic disease. The objective of this study is to investigate the signaling pathways involved in DIO3 upregulation in PTC. Experiments were performed in human PTC cell lines (K1 and TPC-1 cells) or tumor samples. DIO3 mRNA and activity were evaluated by real-time PCR and ion-exchange column chromatography respectively. Western blot analysis was used to determine the levels of D3 protein. DIO3 gene silencing was performed via siRNA transfection. DIO3 mRNA levels and activity were readily detected in K1 (BRAF V6 0 0E ) and, at lower levels, in TPC-1 (RET/PTC1) cells ( P <0.007 and P =0.02 respectively). Similarly, DIO3 mRNA levels were higher in PTC samples harboring the BRAF V600E mutation as compared with those with RET/PTC1 rearrangement or negative for these mutations ( P <0.001). Specific inhibition of BRAF oncogene (PLX4032, 3 μM), MEK (U0126, 10–20 μM) or p38 (SB203580, 10–20 μM) signaling was associated with decreases in DIO3 expression in K1 and TPC-1 cells. Additionally, the blockage of the sonic hedgehog (SHH) pathway by cyclopamine (10 μM) resulted in markedly decreases in DIO3 mRNA levels. Interestingly, siRNA-mediated DIO3 silencing induced decreases on cyclin D1 expression and partial G1 phase cell cycle arrest, thereby downregulating cell proliferation. In conclusion, sustained activation of the MAPK and SHH pathways modulate the levels of DIO3 expression in PTC. Importantly, DIO3 silencing was associated with decreases in cell proliferation, thus suggesting a D3 role in tumor growth and aggressiveness.