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The role of SMAD3 in the genetic predisposition to papillary thyroid carcinoma.
Wang, Yanqiang; He, Huiling; Liyanarachchi, Sandya; Genutis, Luke K; Li, Wei; Yu, Lianbo; Phay, John E; Shen, Rulong; Brock, Pamela; de la Chapelle, Albert.
Afiliación
  • Wang Y; Human Cancer Genetics Program and Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
  • He H; Human Cancer Genetics Program and Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
  • Liyanarachchi S; Human Cancer Genetics Program and Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
  • Genutis LK; Human Cancer Genetics Program and Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
  • Li W; Human Cancer Genetics Program and Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
  • Yu L; Center for Biostatistics, The Ohio State University, Columbus, Ohio, USA.
  • Phay JE; Department of Biomedical Informatics, The Ohio State University, Ohio, Columbus, USA.
  • Shen R; Department of Surgery, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
  • Brock P; Department of Pathology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
  • de la Chapelle A; Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
Genet Med ; 20(9): 927-935, 2018 09.
Article en En | MEDLINE | ID: mdl-29300379
PURPOSE: To identify and characterize the functional variants, regulatory gene networks, and potential binding targets of SMAD3 in the 15q22 thyroid cancer risk locus. METHODS: We performed linkage disequilibrium (LD) and haplotype analyses to fine map the 15q22 locus. Luciferase reporter assays were applied to evaluate the regulatory effects of the candidate variants. Knockdown by small interfering RNA, microarray analysis, chromatin immunoprecipitation (ChIP) and quantitative real-time polymerase chain reaction assays were performed to reveal the regulatory gene network and identify its binding targets. RESULTS: We report a 25.6-kb haplotype within SMAD3 containing numerous single-nucleotide polymorphisms (SNPs) in high LD. SNPs rs17293632 and rs4562997 were identified as functional variants of SMAD3 by luciferase assays within the LD region. These variants regulate SMAD3 transcription in an allele-specific manner through enhancer elements in introns of SMAD3. Knockdown of SMAD3 in thyroid cancer cell lines revealed its regulatory gene network including two upregulated genes, SPRY4 and SPRY4-IT1. Sequence analysis and ChIP assays validated the actual binding of SMAD3 protein to multiple SMAD binding element sites in the region upstream of SPRY4. CONCLUSION: Our data provide a functional annotation of the 15q22 thyroid cancer risk locus.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Tiroides / Proteína smad3 / Cáncer Papilar Tiroideo Límite: Humans Idioma: En Revista: Genet Med Asunto de la revista: GENETICA MEDICA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Tiroides / Proteína smad3 / Cáncer Papilar Tiroideo Límite: Humans Idioma: En Revista: Genet Med Asunto de la revista: GENETICA MEDICA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos