MicroRNAs involved in theHMGA2deregulation and its co-occurrence withMED12mutation in uterine leiomyoma

Abstract

BACKGROUND: Uterine Leiomyoma (UL) is the most common mesenchymal benign tumor associated with several clinical symptoms and elevated number of hysterectomies. The recent stratification of UL, according to recurrent and mutually exclusive genomic alterations affecting HMGA2, MED12, FH and COL4A5-COL4A6, pointed out the involvement of distinct molecular pathways. However, the mechanisms of regulation involving these drivers are poorly explored. METHODS: A total of 78 UL and 34 adjacent normal myometrium (NM) tissues was collected from 56 patients who underwent hysterectomies at a single institution. Gene expression profiling was evaluated from fresh frozen tissues and compared with MED12 mutations at exon 2. In addition, RT-qPCR was applied to evaluate the expression levels of HMGA2 and their predictive miRNA regulators: hsa-let-7a, miR-26a, miR-26b, mir-93 and mir-106b. RESULTS: An unsupervised hierarchical clustering analysis revealed two main clusters with one of them (26 of 42 UL) showing an enrichment of MED12 mutated cases (18 of 26 UL). Increased expression levels of HMGA2 were observed in both clusters, including cases with MED12 mutation (cluster 1: 18 UL). The analysis of RT-qPCR revealed a significant HMGA2 overexpression (p<0.001) in UL in comparison with NM. Five miRNAs predicted to regulate HMGA2 were significantly downregulated (p<0.001) and negatively correlated to HMGA2 expression levels (P<0.05) in UL. CONCLUSION: HMGA2 overexpression was detected in a significant number of MED12 mutated UL, suggesting that these alterations can coexist. Furthermore, five miRNAs were pointed out as potential regulators of HMGA2 expression in UL.

The m6A methyltransferase METTL3 controls epithelial-mesenchymal transition, migration and invasion of breast cancer through the MALAT1/miR-26b/HMGA2 axis

“…The results of these assays verified that MALAT1 does indeed interact with miR-26b and inhibits its expression. Using an online tool, we predicted that miR-26b has a binding site with HMGA2 mRNA 3’UTR, as likewise show by published predictions that hsa-miR-26b is an miRNA regulator of HMGA2 [ 33 ]. Also, Young et.…”

RETRACTED: MiR‐93 blocks cell cycle progression and promotes apoptosis in uterine leiomyoma cells by targeting CCND1

“…As the most common type of benign tumor in the women's reproductive system, uterine leiomyoma (UL) has an incidence rate as high as about 70% during the lifetime of a woman (Wu et al, 2015). One in five patients with UL presents symptoms such as menstrual abnormalities, gynecological disorders, pelvic pressure and pain, habitual abortion, pregnancy complications, even infertility (Mello et al, 2018). In fact, UL has been reported to be the main cause for hysterectomy and myomectomy in clinic settings (Liu et al, 2019).…”

The Role of miRNA and Related Pathways in Pathophysiology of Uterine Fibroids—From Bench to Bedside

“…Various miRNAs, such as hsa-let-7a, hsa-miR-26a, hsa-miR-26b, hsa-miR-93 and hsa-miR-106b, were found to be downregulated and negatively correlated with HMGA2. These authors have concluded that their finding may explain HMGA2 overexpression in UFs and could be an important direction of future research [57].…”

“…Exogenous let-7 miRNAs directly repress the dominant transcript of HMGA2 and HMGA2a [56]. One of the regions of the HMGA gene has 7 complementary sites to hsa-let-7 [57]. In 2018, Mello et al [57] reported the co-occurrence of HMGA2 overexpression and MED12 mutation in UFs.…”

“…One of the regions of the HMGA gene has 7 complementary sites to hsa-let-7 [57]. In 2018, Mello et al [57] reported the co-occurrence of HMGA2 overexpression and MED12 mutation in UFs. These authors have found that the expression of microRNAs predicted to regulate HMGA2.…”