The role of microRNA genes in papillary thyroid carcinoma.
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.
He
Huiling
H
Human Cancer Genetics Program, Department of Pathology, Ohio State University, Columbus, OH 43210, USA.
Jazdzewski
Krystian
K
Li
Wei
W
Liyanarachchi
Sandya
S
Nagy
Rebecca
R
Volinia
Stefano
S
Calin
George A
GA
Liu
Chang-Gong
CG
Franssila
Kaarle
K
Suster
Saul
S
Kloos
Richard T
RT
Croce
Carlo M
CM
de la Chapelle
Albert
A
D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism; D019295:Computational Biology; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000737:chemistry; D015233:Models, Statistical; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012984:Software; D013961:Thyroid Gland / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000628:therapy; D015854:Up-Regulation
D035683:MicroRNAs; D012333:RNA, Messenger; D004247:DNA; D019009:Proto-Oncogene Proteins c-kit