The role of microRNA genes in papillary thyroid carcinoma

Huiling He

Krystian Jazdzewski

Wei Li

Sandya Liyanarachchi

Kaarle Franssila+4 authors

^{Human Cancer Genetics Program,}^{Department of Pathology, and}^{Departments of Internal Medicine and Radiology, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210; and}^{Department of Pathology, Helsinki University Central Hospital, FIN-00029, Helsinki, Finland}

^{To whom correspondence should be addressed. E-mail:}ude.cmuso@ellepahcaled.trebla.

Contributed by Albert de la Chapelle, November 9, 2005

Abstract

Apart from alterations in the RET/PTC-RAS-BRAF pathway, comparatively little is known about the genetics of papillary thyroid carcinoma (PTC). We show that numerous microRNAs (miRNAs) are transcriptionally up-regulated in PTC tumors compared with unaffected thyroid tissue. A set of five miRNAs, including the three most up-regulated ones (miR-221, -222, and -146), distinguished unequivocally between PTC and normal thyroid. Additionally, miR-221 was up-regulated in unaffected thyroid tissue in several PTC patients, presumably an early event in carcinogenesis. Tumors in which the up-regulation (11- to 19-fold) of miR-221, -222, and -146 was strongest showed dramatic loss of KIT transcript and Kit protein. In 5 of 10 such cases, this down expression was associated with germline single-nucleotide changes in the two recognition sequences in KIT for these miRNAs. We conclude that up-regulation of several miRs and regulation of KIT are involved in PTC pathogenesis, and that sequence changes in genes targeted by miRNAs can contribute to their regulation.

Keywords: gene expression, KIT, DNA polymorphism

Abstract

Papillary thyroid carcinoma (PTC) is the most common malignancy in thyroid tissue, accounting for ≈80% of all thyroid cancers. The incidence of PTC in the United States has increased in recent years (1). Genetically, PTC is characterized by alterations in the RET/PTC-RAS-BRAF signaling pathway (2, 3). Activating mutations in BRAF and RET/PTC gene rearrangements are frequent genetic changes in PTC tumors (4–6). A strong inherited genetic predisposition is suggested by case-control studies showing a 3- to 8-fold risk in first-degree relatives, one of the highest of all cancers (7, 8). Despite unequivocal evidence of an inherited predisposition, large families displaying Mendelian inheritance of PTC are rare, and no predisposing gene mutations have been found, even though several putative loci have been identified by linkage analysis (9–11).

MicroRNAs (miRNAs) represent a previously uncharacterized class of gene products that are believed to function as negative regulators of gene expression (12–16). Recently, miRNA genes have been implicated in several cancers (14, 17–25). The expression of miRNAs varies between cancer and normal cells and varies among different types of cancer. In most cancers studied so far, the expression of miRNAs seems to be lower than in the corresponding normal tissue (17, 18, 21, 22, 24).

We reasoned that the previous failure to identify genes predisposing or contributing to PTC might be because these genes show low penetrance. The mechanisms may require the interaction of two or more genes; thus, regulatory, rather than protein-encoding, genes might be involved. We undertook this study to elucidate the role of regulatory genes such as the miRNAs in the predisposition and development of PTC.

A summary of SAM analysis of paired T-PTC and unaffected thyroid tissue from 15 PTC patients. Mean of fold changes; Localfdr, local false discovery rates. q value (%) of all miRNAs was 0.

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Acknowledgments

We thank Jan Lockman and Heejei Yoon for help and advice. This work was supported by National Institutes of Health (NIH) Grants CA16058 (to A.d.l.C.) and P01 CA78890 (to C.M.C.). BRB ArrayTools was developed by Dr. Richard Simon and Amy Peng Lam. Thyroid tissue samples were provided by the Cooperative Human Tissue Network, which is funded by the National Cancer Institute.

Acknowledgments

Notes

Author contributions: H.H., C.M.C., and A.d.l.C. designed research; H.H., K.J., W.L., R.N., C.-G.L., K.F., S.S., and R.T.K. performed research; H.H., K.J., S.L., S.V., G.A.C., and A.d.l.C. analyzed data; and H.H., K.J., and A.d.l.C. wrote the paper.

Conflict of interest statement: No conflicts declared.

Abbreviations: miRNA, microRNA; PTC, papillary thyroid carcinoma; N-PTC, normal thyroid tissue adjacent to PTC tumors; T-PTC, tumor tissue PTC.

Data deposition: Gene expression data with Affymetrix chips were deposited in the National Center for Biotechnology Information Gene Expression Omnibus database (NCBI GEO accession no. GSE3467). MicroRNA chip data have been deposited at the ArrayExpress database (accession no. E-TABM-68).

Notes

Conflict of interest statement: No conflicts declared.

Abbreviations: miRNA, microRNA; PTC, papillary thyroid carcinoma; N-PTC, normal thyroid tissue adjacent to PTC tumors; T-PTC, tumor tissue PTC.

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