Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer

Zhang, Lin; Volinia, Stefano; Bonome, Tomás; Calin, George A.; Greshock, Joel; Yang, Nuo; Liu, Chang Gong; Giannakakis, Antonis; Alexiou, Panagiotis; Hasegawa, Kosei; Johnstone, Cameron N.; Megraw, Molly; Adams, Sarah F.; Lassus, Heini; Huang, Jia; Kaur, Sippy; Liang, Shun; Sethupathy, Praveen; Leminen, Arto; Simossis, Victor A.; Sandaltzopoulos, Raphael; Naomoto, Yoshio; Katsaros, Dionyssios; Gimotty, Phyllis A.; DeMichele, Angela; Huang, Qihong; Bützow, Ralf; Rustgi, Anil K.; Weber, Barbara; Birrer, Michael J.; Hatzigeorgiou, Artemis G.; Croce, Carlo M.; Coukos, George

doi:10.1073/pnas.0801615105

Cited by 468 publications

(449 citation statements)

References 48 publications

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“…Other reports have demonstrated hypermethylation-induced silencing of miR-203 leading to overexpression of oncogenic BcrAbl in chronic myelogenous leukemia (Bueno et al, 2008). Consequently, exposure to decitabine, alone or in combination with histone deacetylase inhibitors restores miRNA expression with corresponding declines in target oncogene expression and apoptosis of neoplastic cells (Calin and Croce, 2006;Mertens et al, 2006;Saito et al, 2006;Zhang et al, 2008). Therefore, as methylation patterns that affect miRNA expression become better understood, opportunities may arise that support the use of select nucleoside analogs to target specific gene expression.…”

Section: Nucleoside Analogs and Micrornamentioning

confidence: 99%

Nucleoside analogs: molecular mechanisms signaling cell death

2008

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Nucleoside analogs are structurally similar antimetabolites that have a broad range of action and are clinically active in both solid tumors and hematological malignancies. Many of these agents are incorporated into DNA by polymerases during normal DNA synthesis, an action that blocks further extension of the nascent strand and causes stalling of replication forks. The molecular mechanisms that sense stalled replication forks activate cell cycle checkpoints and DNA repair processes, which may contribute to drug resistance. When replication forks are not stabilized by these molecules or when subsequent DNA repair processes are overwhelmed, apoptosis is initiated either by these same DNA damage sensors or by alternative mechanisms. Recently, strategies aimed at targeting DNA damage checkpoints or DNA repair processes have demonstrated effectiveness in sensitizing cells to nucleoside analogs, thus offering a means to elude drug resistance. In addition to their DNA synthesisdirected actions many nucleoside analogs trigger apoptosis by unique mechanisms, such as causing epigenetic modifications or by direct activation of the apoptosome. A review of the cellular and molecular responses to clinically relevant agents provides an understanding of the mechanisms that cause apoptosis and may provide rationale for the development of novel therapeutic strategies.

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Section: Nucleoside Analogs and Micrornamentioning

confidence: 99%

Nucleoside analogs: molecular mechanisms signaling cell death

2008

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“…In silico expression and comparative genomic hybridisation analyses Dysregulated miRNAs in ovarian cancer was compiled from eight published studies (Iorio et al, 2007;Bearfoot et al, 2008;Dahiya et al, 2008;Nam et al, 2008;Taylor and Gercel-Taylor, 2008;Zhang et al, 2008;Boren et al, 2009;Resnick et al, 2009). Assessment of KLK protein dysregulation in ovarian cancer was compiled from the results of 17 studies (Dong et al, 2001;Luo et al, 2001Luo et al, , 2003Tanimoto et al, 2001;Hoffman et al, 2002;Yousef et al, , 2003bBorgono et al, 2003;Diamandis et al, 2003;Ni et al, 2004;Scorilas et al, 2004;Xi et al, 2004;Prezas et al, 2006;Shan et al, 2007;Bayani et al, 2008;Shaw and Diamandis, 2008).…”

Section: Bioinformatic Analysismentioning

confidence: 99%

Three dysregulated miRNAs control kallikrein 10 expression and cell proliferation in ovarian cancer

et al. 2010

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BACKGROUND: Kallikrein-related peptidases (KLKs) are a family of serine proteases that have been shown to be dysregulated in several malignancies including ovarian cancer. The control of kallikrein genes and their physiological function in cancer is not well understood. We hypothesized that microRNAs (miRNAs) represent a novel mechanism for post-transcriptional control of KLK expression in cancer. METHODS: We first analysed miRNA expression in ovarian cancer in silico. A total of 98 miRNAs were reported to have altered expression in ovarian cancer. Three of these miRNAs were predicted to target KLK10. We experimentally verified the predicted miR -KLK10 interaction using two independent techniques, a luciferase assay with a construct containing the KLK10 3 0 untranslated region (UTR), pMIR -KLK10, and measuring KLK10 protein levels after transfection with miRNA. RESULTS: When we co-transfected cells with pMIR -KLK10 and either let-7f, miR-224, or mR-516a, we saw decreased luciferase signal, suggesting that these miRNAs can target KLK10. We then examined the effect of these three miRNAs on KLK10 protein expression and cell growth. Transfection of all miRNAs, let-7f, miR-224, and miR-516a led to a decrease in protein expression and cellular growth. This effect was shown to be dose dependent. The KLK10 protein levels were partially restored by co-transfecting let-7f and its inhibitor. In addition, there was a slight decrease in KLK10 mRNA expression after transfection with let-7f. CONCLUSIONS: Our results confirm that KLKs can be targeted by more than one miRNA. Increased expression of certain miRNAs in ovarian cancer can lead to decreased KLK protein expression and subsequently have a negative effect on cell proliferation. This dose-dependent effect suggests that a 'tweaking' or 'fine-tuning' mechanism exists in which the expression of one KLK can be controlled by multiple miRNAs. These data together suggest that miRNA may be used as potential therapeutic options and further studies are required.

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“…In particular, miRNAs are hypothesized to play an important regulatory role in ovarian cancer disease where observations highlighted the deregulation of miRNAs (6). Comparing epithelial ovarian carcinoma with immortalized ovarian surface epithelial cells, the vast majority of miRNA changes occur through downregulation (88.6%) by a combination of genomic copy number loss and epigenetic silencing and these differences are sufficient to distinguish malignant versus nonmalignant ovarian epithelium (7).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-30c-2* Expressed in Ovarian Cancer Cells Suppresses Growth Factor–Induced Cellular Proliferation and Downregulates the Oncogene BCL9

Jia

Eneh

Ratnaparkhe

et al. 2011

Molecular Cancer Research

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MicroRNAs (miRNAs) are small noncoding RNAs that function as master regulators of posttranscriptional gene expression with each miRNA negatively regulating hundreds of genes. Lysophosphatidic acid (LPA) is a mitogenic lipid present within the ovarian tumor microenvironment and induces LPA receptor activation and intracellular signaling cascades like ERK/MAPK, leading to enhanced cellular proliferation. Here, we show that in SKOV-3 and OVCAR-3 cells, LPA stimulation at concentrations ranging from 1 nmol/L to 20 mmol/L for 30 to 60 minutes increases miR-30c-2 Ã , and this effect is mediated through a combination of receptors because knock down of multiple LPA receptors is required for inhibition. The epidermal growth factor and platelet-derived growth factor also increase miR-30c-2 Ã transcript expression, suggesting a broader responsive role for miR-30c-2 Ã . Thus, we investigated the functional role of miR-30c-2 Ã through ectopic expression of synthetic miRNA precursors of mature miRNA or antagomir transfection and observed that microRNA-30c-2 Ã reduces, and the antagomir enhances, cell proliferation and viability in OVCAR-3, cisplatin-insensitive SKOV-3 and chemoresistant HeyA8-MDR cells. Ectopic expression of miR-30c-2 Ã reduces BCL9 mRNA transcript abundance and BCL9 protein. Consistent with this observation, miR-30c-2 Ã ectopic expression also reduced BCL9 luciferase reporter gene expression. In comparison with IOSE cells, all cancer cells examined showed increased BCL9 expression, which is consistent with its role in tumor progression. Taken together, this suggest that growth factor induced proliferation mediates a neutralizing response by significantly increasing miR-30c-2 Ã which reduces BCL9 expression and cell proliferation in SKOV-3 and OVCAR-3 cells, likely as a mechanism to regulate signal transduction downstream. Mol Cancer Res; 9(12); 1732-45. Ó2011 AACR.

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Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer

Cited by 468 publications

References 48 publications

Nucleoside analogs: molecular mechanisms signaling cell death

Nucleoside analogs: molecular mechanisms signaling cell death

Three dysregulated miRNAs control kallikrein 10 expression and cell proliferation in ovarian cancer

MicroRNA-30c-2* Expressed in Ovarian Cancer Cells Suppresses Growth Factor–Induced Cellular Proliferation and Downregulates the Oncogene BCL9

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