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miRNA profiling along tumour progression in ovarian carcinoma
Olga Vaksman1, Helene Tuft Stavnes, Janne Kaern
1Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Abstract:
MicroRNAs (miRNAs) are small non-coding RNAs that exert a regulatory effect post-transcriptionally by binding target mRNAs and inhibiting gene translation. miRNA expression is deregulated in cancer. The aim of this study was to characterize the differences in miRNA expression pattern and the miRNA-regulating machinery between ovarian carcinoma (OC) cells in primary tumours versus effusions. Using miRNA array platforms, we analysed a set of 21 tumours (13 effusions, 8 primary carcinomas) and identified three sets of miRNAs, one that is highly expressed in both primary carcinomas and effusions, one overexpressed in primary carcinomas and one overexpressed in effusions. Levels of selected miRNAs were analysed using quantitative PCR in an independent set of 45 additional tumours (30 effusions, 15 primary carcinomas). Reduced miR-145 and miR-214 and elevated let-7f, miR-182, miR-210, miR-200c, miR-222 and miR-23a levels were found in effusions in both sets. In silico target prediction programs identified potential target genes for some of the differentially expressed miRNAs. Expression of zinc finger E-box binding homeobox (ZEB)1 and c-Myc, targets of miR-200c, as well as of p21 protein (Cdc42/Rac)-activated kinase (PAK)1 and phosphatase and tensin homologue deleted on chromosome 10 (PTEN), predicted targets of miR-222, were analysed. Inverse correlations between expression levels of the indicated miRNAs and of the predicted target genes were found. In addition, higher expression of the miRNA-processing molecules Ago1, Ago2 and Dicer was observed in effusions compared to primary carcinomas. In conclusion, our data are the first to document different miRNA expression and regulation profiles in primary and metastatic OC, suggesting a role for these molecules in tumour progression.
Insights
MicroRNA (miRNA) expression differs between primary ovarian cancer and metastatic effusions. This suggests distinct miRNA roles in ovarian cancer progression and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MicroRNAs (miRNAs) are small non-coding RNAs regulating gene expression post-transcriptionally.
- Dysregulated miRNA expression is a hallmark of cancer, including ovarian carcinoma (OC).
- Understanding miRNA differences between primary tumors and metastatic sites is crucial for cancer progression insights.
Purpose of the Study:
- To characterize differential miRNA expression profiles between primary OC and OC cells in malignant effusions.
- To investigate the miRNA-regulating machinery in primary versus metastatic OC.
- To identify potential miRNA targets and their role in OC progression.
Main Methods:
- miRNA expression profiling using array platforms on 21 OC tumors (8 primary, 13 effusions).
- Quantitative PCR validation of selected miRNAs in an independent cohort of 45 OC tumors (15 primary, 30 effusions).
- In silico target prediction and analysis of target gene expression (ZEB1, c-Myc, PAK1, PTEN) and miRNA-processing enzymes (Ago1, Ago2, Dicer).
Main Results:
- Identified distinct miRNA expression patterns: some miRNAs highly expressed in both primary and effusion tumors, others overexpressed in primary tumors, and a third set overexpressed in effusions.
- Specific miRNAs (e.g., miR-145, miR-214) were reduced, while others (e.g., let-7f, miR-182, miR-210, miR-200c, miR-222, miR-23a) were elevated in effusions compared to primary tumors.
- Higher expression of miRNA-processing enzymes (Ago1, Ago2, Dicer) was observed in effusions versus primary carcinomas, alongside inverse correlations between specific miRNAs and their predicted targets (ZEB1, c-Myc, PAK1, PTEN).
Conclusions:
- This study provides the first evidence of distinct miRNA expression and regulatory profiles in primary versus metastatic OC.
- The observed differences suggest a significant role for miRNAs in ovarian cancer progression and metastasis.
- Altered miRNA machinery and expression in effusions may contribute to the metastatic phenotype of OC.
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