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PMID: 22586128 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

The polymorphism rs944289 predisposes to papillary thyroid carcinoma through a large intergenic noncoding RNA gene of tumor suppressor type.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 109 ·No. 22 ·2012-05-29 ·Pages 8646-51

Jendrzejewski J, He H, Radomska HS, Li W, Tomsic J, Liyanarachchi S, Davuluri RV, Nagy R, de la Chapelle A

Abstract

A genome-wide association study of papillary thyroid carcinoma (PTC) pinpointed two independent SNPs (rs944289 and rs965513) located in regions containing no annotated genes (14q13.3 and 9q22.33, respectively). Here, we describe a unique, long, intergenic, noncoding RNA gene (lincRNA) named Papillary Thyroid Carcinoma Susceptibility Candidate 3 (PTCSC3) located 3.2 kb downstream of rs944289 at 14q.13.3 and the expression of which is strictly thyroid specific. By quantitative PCR, PTCSC3 expression was strongly down-regulated (P = 2.84 × 10(-14)) in thyroid tumor tissue of 46 PTC patients and the risk allele (T) was associated with the strongest suppression (genotype [TT] (n = 21) vs. [CT] (n = 19), P = 0.004). In adjacent unaffected thyroid tissue, the genotype [TT] was associated with up-regulation of PTCSC3 ([TT] (n = 21) vs. [CT] (n = 19), P = 0.034). The SNP rs944289 was located in a binding site for the CCAAT/enhancer binding proteins (C/EBP) α and β. The risk allele destroyed the binding site in silico. Both C/EBPα and C/EBPβ activated the PTCSC3 promoter in reporter assays (P = 0.0009 and P = 0.0014, respectively) and the risk allele reduced the activation compared with the nonrisk allele (C) (P = 0.026 and P = 0.048, respectively). Restoration of PTCSC3 expression in PTC cell line cells (TPC-1 and BCPAP) inhibited cell growth (P = 0.002 and P = 0.019, respectively) and affected the expression of genes involved in DNA replication, recombination and repair, cellular movement, tumor morphology, and cell death. Our data suggest that SNP rs944289 predisposes to PTC through a previously uncharacterized, long intergenic noncoding RNA gene (PTCSC3) that has the characteristics of a tumor suppressor.

MeSH Terms
Animals Binding Sites/genetics Blotting, Northern CCAAT-Enhancer-Binding Protein-beta/metabolism COS Cells Carcinoma, Papillary/genetics,pathology Cell Line, Tumor Cell Proliferation Chlorocebus aethiops Chromosomes, Human, Pair 14/genetics Gene Expression Profiling Gene Expression Regulation, Neoplastic Genes, Tumor Suppressor Genetic Predisposition to Disease/genetics Genotype HEK293 Cells Humans Molecular Sequence Data Oligonucleotide Array Sequence Analysis Polymorphism, Single Nucleotide RNA, Untranslated/genetics Reverse Transcriptase Polymerase Chain Reaction Thyroid Neoplasms/genetics,pathology
Chemicals
CCAAT-Enhancer-Binding Protein-beta RNA, Untranslated
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Jendrzejewski Jaroslaw
Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
He Huiling
Radomska Hanna S
Li Wei
Tomsic Jerneja
Liyanarachchi Sandya
Davuluri Ramana V
Nagy Rebecca
de la Chapelle Albert
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1205654109
Published
2012-05-29
Epub
2012-00-14
Pages
8646-51
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3365219
Subset
IM
Grants
NCI NIH HHS · P01 CA124570 · United States
NCI NIH HHS · P30 CA016058 · United States
NCI NIH HHS · P01CA124570 · United States
NCI NIH HHS · P30CA16058 · United States
Databases
GENBANK
JN689234
GEO
GSE32195
External Links
PubMed source DOI: 10.1073/pnas.1205654109 PMC Full Text View journal details
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