Oncogenic role of miR-17-92 cluster in anaplastic thyroid cancer cells.
Micro RNAs (miRNAs) are non-coding small RNAs and constitute a novel class of negative gene regulators that are found in both plants and animals. Several miRNAs play crucial roles in cancer cell growth. To identify miRNAs specifically deregulated in anaplastic thyroid cancer (ATC) cells, we performed a comprehensive analysis of miRNA expressions in ARO cells and primary thyrocytes using miRNA microarrays. MiRNAs in a miR-17-92 cluster were overexpressed in ARO cells. We confirmed the overexpression of those miRNAs by Northern blot analysis in ARO and FRO cells. In 3 of 6 clinical ATC samples, miR-17-3p and miR-17-5p were robustly overexpressed in cancer lesions compared to adjacent normal tissue. To investigate the functional role of these miRNAs in ATC cells, ARO and FRO cells were transfected with miRNA inhibitors, antisense oligonucleotides containing locked nucleic acids. Suppression of miR-17-3p caused complete growth arrest, presumably due to caspase activation resulting in apoptosis. MiR-17-5p or miR-19a inhibitor also induced strong growth reduction, but only miR-17-5p inhibitor led to cellular senescence. On the other hand, miR-18a inhibitor only moderately attenuated the cell growth. Thus, we have clarified functional differences among the members of the cluster in ATC cells. In conclusion, these findings suggest that the miR-17-92 cluster plays an important role in certain types of ATCs and could be a novel target for ATC treatment.
Takakura
Shu
S
Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
Mitsutake
Norisato
N
Nakashima
Masahiro
M
Namba
Hiroyuki
H
Saenko
Vladimir A
VA
Rogounovitch
Tatiana I
TI
Nakazawa
Yuka
Y
Hayashi
Tomayoshi
T
Ohtsuru
Akira
A
Yamashita
Shunichi
S
D017209:Apoptosis / Q000502:physiology; D015152:Blotting, Northern; D015153:Blotting, Western; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D015536:Down-Regulation; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009857:Oncogenes / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
D008565:Membrane Proteins; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; C446603:TPTE protein, human; D051059:PTEN Phosphohydrolase; D020169:Caspases