Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer - PubMed (original) (raw)

. 2008 May 13;105(19):7004-9.

doi: 10.1073/pnas.0801615105. Epub 2008 May 5.

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

Affiliations

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

Lin Zhang et al. Proc Natl Acad Sci U S A. 2008.

Abstract

MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs that function as negative gene regulators. miRNA deregulation is involved in the initiation and progression of human cancer; however, the underlying mechanism and its contributions to genome-wide transcriptional changes in cancer are still largely unknown. We studied miRNA deregulation in human epithelial ovarian cancer by integrative genomic approach, including miRNA microarray (n = 106), array-based comparative genomic hybridization (n = 109), cDNA microarray (n = 76), and tissue array (n = 504). miRNA expression is markedly down-regulated in malignant transformation and tumor progression. Genomic copy number loss and epigenetic silencing, respectively, may account for the down-regulation of approximately 15% and at least approximately 36% of miRNAs in advanced ovarian tumors and miRNA down-regulation contributes to a genome-wide transcriptional deregulation. Last, eight miRNAs located in the chromosome 14 miRNA cluster (Dlk1-Gtl2 domain) were identified as potential tumor suppressor genes. Therefore, our results suggest that miRNAs may offer new biomarkers and therapeutic targets in epithelial ovarian cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Numerous miRNAs are down-regulated in late-stage or high-grade ovarian cancer. (A) Heat map showing the 44 miRNAs significantly down-regulated in late-stage relative to early-stage EOC. (B) Heat map showing the 13 miRNAs significantly down-regulated in high-grade relative to low-grade EOC. (C) Heat map showing the miRNAs significantly down-regulated in late-stage or high-grade serous EOC. (D) Venn diagrams of down-regulated miRNAs in different analyses.

Fig. 2.

Fig. 2.

DNA copy number deletions contribute to down-regulation of miRNAs. (A) DNA copy number status of 17 genomic loci containing miRNAs differentially expressed between IOSE cells and EOC cell lines. (Upper) Four up-regulated miRNAs. (Lower) Thirteen down-regulated miRNAs. Red lines indicate the designated cut-off for significant alterations (20%). (B) DNA copy number status of 16 genomic loci containing miRNAs significantly down-regulated in late-stage EOC. Red lines indicate the designated cut-off for significant alterations (20%).

Fig. 3.

Fig. 3.

Epigenetic alterations silence miRNA expression in ovarian cancer. (A) Heat map depicts expression of 24 miRNAs in IOSE cells and EOC cell lines analyzed by real-time RT-PCR. (B) Expression of the same 24 miRNAs in five EOC cell lines and HeLa cells after treatment with demethylating agent 5-aza-2′-deoxycytidine (5-Aza-CdR) and the histone deacetylase inhibitor 4-phenylbutyric acid (PBA) for 6 days.

Fig. 4.

Fig. 4.

miRNA deregulation affects mRNA transcripts. Histograms of negative natural logarithms of 4,096 P values derived from one-tailed Wilcoxon rank sum test applied to the distributions of each hexamer occurrence in the 3′ UTRs of all up-regulated versus unchanged mRNA transcripts.

Fig. 5.

Fig. 5.

Down-regulation of miRNA cluster at the Dlk1-Gtl2 domain is associated with poor survival. (A) Nonsupervised clustering of the eight Dlk1-Gtl2 domain miRNA expression signatures classifies 73 late-stage EOC in two distinct clusters (cluster 1, n = 38; cluster 2, n = 35). (B) Five-year survival of patients with advanced stage EOC whose tumors belong to cluster 1 (blue) or cluster 2 (green). (C) Summary of clinicopathologic characteristics of patients in the two clusters. (D) Examples of high and low proliferation index based on Ki67 immunohistochemistry staining in late-stage EOC. (E) Summary of proliferation index in tumors from the two clusters.

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