MicroRNA profiling of benign and malignant pheochromocytomas identifies novel diagnostic and therapeutic targets.
MicroRNAs (miRNAs) are small RNAs ( approximately 22 bp) that post-transcriptionally regulate protein expression and are found to be differentially expressed in a number of human cancers. There is increasing evidence to suggest that miRNAs could be useful in cancer diagnosis, prognosis, and therapy. We performed miRNA microarray expression profiling on a cohort of 12 benign and 12 malignant pheochromocytomas and identified a number of differentially expressed miRNAs. These results were validated in a separate cohort of ten benign and ten malignant samples using real-time quantitative RT-PCR; benign samples had a minimum follow-up of at least 2 years. It was found that IGF2 as well as its intronic miR-483-5p was over-expressed, while miR-15a and miR-16 were under-expressed in malignant tumours compared with benign tumours. These miRNAs were found to be diagnostic and prognostic markers for malignant pheochromocytoma. The functional role of miR-15a and miR-16 was investigated in vitro in the rat PC12 pheochromocytoma cell line, and these miRNAs were found to regulate cell proliferation via their effect on cyclin D1 and apoptosis. These data indicate that miRNAs play a pivotal role in the biology of malignant pheochromocytoma, and represent an important class of diagnostic and prognostic biomarkers and therapeutic targets warranting further investigation.
Meyer-Rochow
Goswin Y
GY
Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Department of Endocrine and Oncology Surgery, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia.
Jackson
Nicole E
NE
Conaglen
John V
JV
Whittle
Denis E
DE
Kunnimalaiyaan
Muthusamy
M
Chen
Herbert
H
Westin
Gunnar
G
Sandgren
Johanna
J
Stålberg
Peter
P
Khanafshar
Elham
E
Shibru
Daniel
D
Duh
Quan-Yang
QY
Clark
Orlo H
OH
Kebebew
Electron
E
Gill
Anthony J
AJ
Clifton-Bligh
Rory
R
Robinson
Bruce G
BG
Benn
Diana E
DE
Sidhu
Stan B
SB
D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle; D015331:Cohort Studies; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger