CONTEXT: Loss of the thyroid hormone receptor is common in tumors. In mouse models, a truncated THRB gene leads to thyroid cancer. Previously, we observed up-regulation of the expression of eight microRNAs (miRs) in papillary thyroid carcinoma (PTC) tumors. OBJECTIVE: Our objective was to determine whether THRB might be inhibited by miRs up-regulated in PTC. DESIGN: The potential binding of miR to the 3'-untranslated region of THRB was analyzed in silico. Direct inhibition by miRs binding to the cloned 3'-untranslated region of THRB was evaluated using luciferase assays. Inhibition of endogenous THRB and its target genes (DIO1 and APP) was examined in cell lines transfected by pre-miRs. The impact on thyroid hormone response element (TRE) was evaluated in promoter assays. Correlations between the expression of THRB and miRs was evaluated in 13 PTC tumor/normal tissue pairs. RESULTS: THRB contains binding sites for the top seven miRs up-regulated in PTC (P = 0.0000002). Direct interaction with THRB was shown for miR-21 and miR-146a. We observed lower levels of THRB transcripts in cell lines transfected with miR-21, -146a, and -221 (down-regulation of 37-48%; P < 0.0001), but not with miR-181a. THRB protein was suppressed down to 10-28% by each of four miRs. Concomitant expression of DIO1 and APP was affected (down-regulation of 32-66%, P < 0.0034 and up-regulation of 48-57%, P < 0.0002, respectively). All four miRs affected TRE activity in promoter assays. Down-regulation of luciferase occurred after transfection with pTRE-TK-Luc construct and each of four miRs. The analysis of tumor/normal tissue pairs revealed down-regulation of THRB in 11 of 13 pairs (1.3- to 9.1-fold), and up-regulation of miR-21, -146a, -181a, and -221 in almost all pairs. CONCLUSIONS: MiRs up-regulated in PTC tumors directly inhibit the expression of THRB, an important tumor suppressor gene.
CONTEXT: Loss of the thyroid hormone receptor is common in tumors. In mouse models, a truncated THRB gene leads to thyroid cancer. Previously, we observed up-regulation of the expression of eight microRNAs (miRs) in papillary thyroid carcinoma (PTC) tumors. OBJECTIVE: Our objective was to determine whether THRB might be inhibited by miRs up-regulated in PTC. DESIGN: The potential binding of miR to the 3'-untranslated region of THRB was analyzed in silico. Direct inhibition by miRs binding to the cloned 3'-untranslated region of THRB was evaluated using luciferase assays. Inhibition of endogenous THRB and its target genes (DIO1 and APP) was examined in cell lines transfected by pre-miRs. The impact on thyroid hormone response element (TRE) was evaluated in promoter assays. Correlations between the expression of THRB and miRs was evaluated in 13 PTC tumor/normal tissue pairs. RESULTS:THRB contains binding sites for the top seven miRs up-regulated in PTC (P = 0.0000002). Direct interaction with THRB was shown for miR-21 and miR-146a. We observed lower levels of THRB transcripts in cell lines transfected with miR-21, -146a, and -221 (down-regulation of 37-48%; P < 0.0001), but not with miR-181a. THRB protein was suppressed down to 10-28% by each of four miRs. Concomitant expression of DIO1 and APP was affected (down-regulation of 32-66%, P < 0.0034 and up-regulation of 48-57%, P < 0.0002, respectively). All four miRs affected TRE activity in promoter assays. Down-regulation of luciferase occurred after transfection with pTRE-TK-Luc construct and each of four miRs. The analysis of tumor/normal tissue pairs revealed down-regulation of THRB in 11 of 13 pairs (1.3- to 9.1-fold), and up-regulation of miR-21, -146a, -181a, and -221 in almost all pairs. CONCLUSIONS: MiRs up-regulated in PTC tumors directly inhibit the expression of THRB, an important tumor suppressor gene.
Authors: George Adrian Calin; Calin Dan Dumitru; Masayoshi Shimizu; Roberta Bichi; Simona Zupo; Evan Noch; Hansjuerg Aldler; Sashi Rattan; Michael Keating; Kanti Rai; Laura Rassenti; Thomas Kipps; Massimo Negrini; Florencia Bullrich; Carlo M Croce Journal: Proc Natl Acad Sci U S A Date: 2002-11-14 Impact factor: 11.205
Authors: Zheng Li; Zhen Hang Meng; Raman Chandrasekaran; Wen-Lin Kuo; Colin C Collins; Joe W Gray; Shanaz H Dairkee Journal: Cancer Res Date: 2002-04-01 Impact factor: 12.701
Authors: Adam Master; Anna Wójcicka; Agnieszka Piekiełko-Witkowska; Joanna Bogusławska; Piotr Popławski; Zbigniew Tański; Veerle M Darras; Graham R Williams; Alicja Nauman Journal: Biochim Biophys Acta Date: 2010-08-03
Authors: F Rosignolo; V Maggisano; M Sponziello; M Celano; C R T Di Gioia; M D'Agostino; L Giacomelli; A Verrienti; M Dima; V Pecce; C Durante Journal: J Endocrinol Invest Date: 2015-05-24 Impact factor: 4.256