Molecular profiling uncovers a p53-associated role for microRNA-31 in inhibiting the proliferation of serous ovarian carcinomas and other cancers.
MicroRNAs (miRNA) regulate complex patterns of gene expression, and the relevance of altered miRNA expression to ovarian cancer remains to be elucidated. By comprehensively profiling expression of miRNAs and mRNAs in serous ovarian tumors and cell lines and normal ovarian surface epithelium, we identified hundreds of potential miRNA-mRNA targeting associations underlying cancer. Functional overexpression of miR-31, the most underexpressed miRNA in serous ovarian cancer, repressed predicted miR-31 gene targets including the cell cycle regulator E2F2. MIR31 and CDKN2A, which encode p14(ARF) and p16(INK4A), are located at 9p21.3, a genomic region commonly deleted in ovarian and other cancers. p14(ARF) promotes p53 activity, and E2F2 overexpression in p53 wild-type cells normally leads via p14(ARF) to an induction of p53-dependent apoptosis. In a number of serous cancer cell lines with a dysfunctional p53 pathway (i.e., OVCAR8, OVCA433, and SKOV3), miR-31 overexpression inhibited proliferation and induced apoptosis; however, in other lines (i.e., HEY and OVSAYO) with functional p53, miR-31 had no effect. Additionally, the osteosarcoma cell line U2OS and the prostate cancer cell line PC3 (p14(ARF)-deficient and p53-deficient, respectively) were also sensitive to miR-31. Furthermore, miR-31 overexpression induced a global gene expression pattern in OVCAR8 associated with better prognosis in tumors from patients with advanced stage serous ovarian cancer, potentially affecting many genes underlying disease progression. Our findings reveal that loss of miR-31 is associated with defects in the p53 pathway and functions in serous ovarian cancer and other cancers, suggesting that patients with cancers deficient in p53 activity might benefit from therapeutic delivery of miR-31.
Creighton
Chad J
CJ
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Fountain
Michael D
MD
Yu
Zhifeng
Z
Nagaraja
Ankur K
AK
Zhu
Huifeng
H
Khan
Mahjabeen
M
Olokpa
Emuejevoke
E
Zariff
Azam
A
Gunaratne
Preethi H
PH
Matzuk
Martin M
MM
Anderson
Matthew L
ML
D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009367:Neoplasm Staging; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D004273:DNA, Neoplasm; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53