Genomic imbalances are involved in miR-30c and let-7a deregulation in ovarian tumors: implications for HMGA2 expression

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.

Keywords: FHIT; HMGA2; LIN28A; let-7a; miR-30c.

Figure 1. Relative normalized expression of HMGA2, LIN28A, and FHIT as well as the miRNAs miR-30c and let-7a

The relative expression of HMGA2 (A), LIN28A (D), FHIT (E) and the miRNAs let-7a (B) and miR-30c (C) is correlated with histotype.

Figure 2. FISH analyses of the let-7a and miR-30c clusters

A signal pattern indicating heterozygous deletion is seen of MIR30C1 on 1p34.2 (A), MIR30C2 on 6q13 (B), MIRLETA1 on 9q22 (C), MIRLET7A2 on 11q24, and MIRLET7A on 22q13 (D).