Molecular profiling uncovers a p53-associated role for microRNA-31 in inhibiting the proliferation of serous ovarian carcinomas and other cancers.
Molecular profiling uncovers a p53-associated role for microRNA-31 in inhibiting the proliferation of serous ovarian carcinomas and other cancers.
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DOI：
10.1158/0008-5472.can-09-3875
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发表时间：
2010-03-01
期刊：
影响因子：
11.2
通讯作者：
Anderson ML
中科院分区：
文献类型：
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作者：
Creighton CJ;Fountain MD;Yu Z;Nagaraja AK;Zhu H;Khan M;Olokpa E;Zariff A;Gunaratne PH;Matzuk MM;Anderson ML
microRNAs（miRNAs）调节基因表达的复杂模式，并且改变的miRNAs表达与卵巢癌的相关性仍有待阐明。通过全面分析浆液性卵巢肿瘤和细胞系以及正常卵巢表面上皮中的miRNAs和mRNAs的表达，我们确定了数百种潜在的miRNA-mRNA靶向癌症相关性。miR-31（浆液性卵巢癌中表达最低的miRNA）的功能性过表达抑制了预测的miR-31基因靶点，包括细胞周期调节因子E2 F2。MIR 31和编码p14 ARF和p16 INK 4A的CDKN 2A位于9p21.3，这是一个在卵巢癌和其他癌症中通常缺失的基因组区域。p14 ARF促进p53活性，并且在p53野生型细胞中E2 F2过表达通常通过p14 ARF导致p53依赖性凋亡的诱导。在许多具有功能失调的p53途径的浆液性癌细胞系中（即，OVCAR 8、OVCA 433和SKOV 3），miR-31过表达抑制增殖并诱导凋亡;然而，在其他细胞系中（即，HEY和OVSAYO）与功能性p53、miR-31没有作用。此外，骨肉瘤细胞系U2 OS和前列腺癌细胞系PC 3（分别为p14 ARF缺陷型和p53缺陷型）也对miR-31敏感。此外，miR-31过表达诱导OVCAR 8中的全局基因表达模式，与晚期浆液性卵巢癌患者的肿瘤预后更好相关，可能影响疾病进展的许多基因。我们的研究结果表明，miR-31的缺失与浆液性卵巢癌和其他癌症中p53通路和功能的缺陷有关，这表明p53活性缺陷的癌症患者可能受益于miR-31的治疗递送。
MicroRNAs (miRNAs) 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 cell cycle regulator E2F2. MIR31 and CDKN2A, which encodes p14ARF and p16INK4A, are located at 9p21.3, a genomic region commonly deleted in ovarian and other cancers. p14ARF promotes p53 activity, and E2F2 overexpression in p53 wild-type cells normally leads via p14ARF 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 (p14ARF-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 impacting 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.