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.
Highlights
Tumors of the ovary are a heterogeneous group which is divided into many different subentities based on histologic and cytologic features
We 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
Summary
Tumors of the ovary are a heterogeneous group which is divided into many different subentities based on histologic and cytologic features. Malignant epithelial ovarian tumors are currently divided into high-grade serous, low-grade serous, endometrioid, mucinous, and clear cell carcinomas [1]. Each carcinoma histotype is characterized by different genetic aberrations. Serous high-grade carcinomas are associated with TP53 and BRCA mutations, whereas their low-grade counterparts often carry KRAS and BRAF mutations. Borderline tumors of the ovary are neoplasms of low or uncertain malignant potential. They present cellular atypia but are not invasive [4]. Sex-cord stromal tumors account for 8% of all ovarian tumors; thecofibromas and fibromas are among the most common tumors of this type [5] whose genetic features remain largely unknown. Some nonrandom chromosomal aberrations have been reported with trisomy and/or tetrasomy 12 as the most common aneuploidies in thecofibromas, followed by trisomy for chromosomes 10, 18, 4, and 9 [6]
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