MiR-182 overexpression in tumourigenesis of high-grade serous ovarian carcinoma.
Molecular pathogenesis of high-grade serous ovarian carcinoma (HG-SOC) is poorly understood. Recent recognition of HG-SOC precursor lesions, defined as serous tubal intraepithelial carcinoma (STIC) in fimbria, provides a new venue for the study of early genetic changes in HG-SOC. Using microRNA profiling analysis, we found that miR-182 expression was significantly higher in STIC than in matched normal Fallopian tube. Further study revealed that miR-182 was significantly overexpressed in most HG-SOC cases. To test whether miR-182 plays a major role in early tumourigenesis of HG-SOC, we overexpressed miR-182 in immortalized ovarian surface, Fallopian tube secretory cells and malignant ovarian cell lines, and found that miR-182 overexpression resulted in increased tumour transformation in vitro, and enhanced tumour invasiveness in vitro and metastasis in vivo. Mechanistically, we demonstrated that the oncogenic properties of miR-182 in ovarian cancer were mediated in part by its impaired repair of DNA double-strand breaks and negative regulation of breast cancer 1 (BRCA1) and metastasis suppressor 1 (MTSS1) expression as well as its positive regulation of the oncogene high-mobility group AT-hook 2 (HMGA2). Our findings suggest that miR-182 dysregulation confers powerful oncogenic potential in the tumourigenesis of HG-SOC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Department of Pathology, Northwestern University School of Medicine, Chicago, IL 60611, USA.
Zhaojian
Z
Liu
Jinsong
J
Liu
Miguel F
MF
Segura
Changshun
C
Shao
Peng
P
Lee
Yaoqin
Y
Gong
Eva
E
Hernando
Jian-Jun
JJ
Wei
D019313:BRCA1 Protein / Q000235:genetics; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003094:Collagen; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004338:Drug Combinations; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000235:genetics; D006801:Humans; D007797:Laminin; D035683:MicroRNAs / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D011509:Proteoglycans; D012189:Retrospective Studies; D046888:Tissue Array Analysis; D014410:Tumor Stem Cell Assay / Q000379:methods; D015854:Up-Regulation
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004338:Drug Combinations; D025743:HMGA2 Protein; D007797:Laminin; C486778:MTSS1 protein, human; D035683:MicroRNAs; D008840:Microfilament Proteins; C538984:Mirn182 microRNA, human; D009363:Neoplasm Proteins; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen