Related Experiment Videos
Genomic imbalances are involved in miR-30c and let-7a deregulation in ovarian tumors: implications for HMGA2
Antonio Agostini1,2, Marta Brunetti1,2, Ben Davidson3,4
1Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Abstract:
The High-mobility group AT-hook 2 protein (HMGA2) is involved in different processes during tumorigenesis. High expression levels of HMGA2 are found in various types of cancer, with recent studies highlighting the important role of miRNAs in the regulation of HMGA2 expression. We report a study of 155 ovarian tumors (30 sex-cord stromal tumors, 22 borderline tumors, and 103 carcinomas) analyzed for HMGA2 expression as well as the expression of two miRNAs targeting this gene, let-7a and miR-30c. We also evaluated the expression of the fragile histidine triad (FHIT) and lin28 homologues (LIN28A/B) genes which are known to be an enhancer of miR-30c expression and a repressor of let-7a, respectively. HMGA2 was found expressed at high levels in most samples analyzed, with clear cell carcinomas as the only exception. let-7a and miR-30c were highly deregulated in all tumor types. LIN28A and FHIT were found overexpressed in all examined tumor types. The chromosomal imbalances that might lead to loss of the genes expressing let-7a and miR-30c could be evaluated on the basis of previously generated karyotypic and high resolution comparative genomic hybridization (CGH) data on 103 tumors. 76% of the samples with an imbalanced genome had at least one chromosomal aberration leading to a deletion of a miRNA cluster for let-7a and miR-30c. FISH using locus specific probes for these clusters validate the aberrations at the gene level. Our study shows that genomic imbalances are involved in miR-30c and let-7a deregulation. One can reasonably assume that dysregulation of these miRNAs is a cause leading to HMGA2 upregulation in ovarian tumors.
Insights
High-mobility group AT-hook 2 protein (HMGA2) is upregulated in most ovarian tumors due to deregulation of let-7a and miR-30c microRNAs. Genomic imbalances contribute to this miRNA dysregulation, impacting HMGA2 expression in cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- High-mobility group AT-hook 2 protein (HMGA2) is implicated in tumorigenesis and frequently overexpressed in cancers.
- MicroRNAs (miRNAs) are crucial regulators of gene expression, including HMGA2.
- let-7a and miR-30c are key miRNAs targeting HMGA2, while LIN28A and FHIT influence their expression.
Purpose of the Study:
- To investigate HMGA2 expression and the roles of let-7a and miR-30c in 155 ovarian tumors.
- To evaluate the expression of FHIT and LIN28A/B in relation to let-7a and miR-30c.
- To determine the impact of genomic imbalances on miRNA deregulation in ovarian cancer.
Main Methods:
- Analysis of HMGA2, let-7a, miR-30c, FHIT, and LIN28A/B expression in ovarian tumor samples.
- Utilizing karyotypic and comparative genomic hybridization (CGH) data to assess chromosomal imbalances.
- Employing Fluorescence In Situ Hybridization (FISH) to validate gene-level aberrations.
Main Results:
- HMGA2 was highly expressed in most ovarian tumors, except clear cell carcinomas.
- let-7a and miR-30c showed significant deregulation across all tumor types.
- LIN28A and FHIT were overexpressed, and 76% of tumors with genomic imbalances had deletions affecting miRNA clusters.
Conclusions:
- Genomic imbalances play a significant role in the deregulation of miR-30c and let-7a in ovarian tumors.
- Dysregulation of these miRNAs is a likely cause of HMGA2 upregulation in ovarian cancer.
- This study highlights the intricate interplay between genomic alterations, miRNA regulation, and oncogene expression in ovarian tumorigenesis.