CIPE-International Research Center-AC Camargo Cancer Center, Sao Paulo, SP, Brazil.
Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
Mol Hum Reprod. 2018 Nov 1;24(11):556-563. doi: 10.1093/molehr/gay037.
Can the mediator complex subunit 12 (MED12) mutation and high mobility group AT-hook 2 (HMGA2) overexpression co-occurrence be explained by the alternative mechanism of HMGA2 dysregulation in uterine leiomyomas (UL)?
The co-occurrence of MED12 mutation and HMGA2 overexpression, and a negative correlation of five validated or predicted microRNAs that target HMGA2 were reported.
The recent stratification of UL, according to recurrent and mutually exclusive genomic alterations affecting HMGA2, MED12, fumarate hydratase (FH) and collagen type IV alpha 5-alpha 6 (COL4A5-COL4A6) pointed out the involvement of distinct molecular pathways. However, the mechanisms of regulation involving these drivers are poorly explored.
STUDY DESIGN, SIZE, DURATION: A total of 78 UL and 34 adjacent normal myometrium (NM) tissues was collected from 56 patients who underwent hysterectomies at a single institution. The patients were treated at the Department of Gynecology and Obstetrics, School of Medicine, Sao Paulo State University, Botucatu, SP, Brazil, from October 1995 to February 2004.
PARTICIPANTS/MATERIALS, SETTING, METHODS: 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.
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). A significant HMGA2 overexpression (P < 0.001) in UL in comparison with NM was found. Five miRNAs predicted to regulate HMGA2 were significantly downregulated (P < 0.001) and negatively correlated to HMGA2 expression levels (P < 0.05) in UL.
An in vivo functional study was not performed to validate the microRNAs and HMGA2 interaction due to technical limitations.
HMGA2 overexpression was detected in a significant number of MED12 mutated ULs, suggesting that these alterations coexist. Furthermore, five miRNAs were described as potential regulators of HMGA2 expression in UL.
LARGE-SCALE DATA: Data available in the Gene Expression Omnibus GSE42939.
STUDY FUNDING AND COMPETING INTEREST(S): This study was supported by grants from Fundação de Amparo a Pesquisa do Estado de São Paulo (# 2008/58835-2) and Conselho Nacional de Pesquisa (# 485032/2007-4), Brazil. The authors declared having no conflicts of interest.
在子宫平滑肌瘤（UL）中，MED12 突变和高迁移率族 AT 钩 2（HMGA2）过表达的共存是否可以通过 HMGA2 失调的替代机制来解释？
报告了 MED12 突变和 HMGA2 过表达的共存，以及五个验证或预测的靶向 HMGA2 的 microRNA 的负相关。
根据影响 HMGA2、MED12、富马酸水合酶（FH）和胶原蛋白类型 IV alpha 5-alpha 6（COL4A5-COL4A6）的复发性和相互排斥的基因组改变对 UL 的最近分层指出了不同分子途径的参与。然而，涉及这些驱动因素的调节机制仍未得到充分探索。
研究设计、大小和持续时间：从在巴西圣保罗马托格罗索州立大学博图卡图医学院妇科接受子宫切除术的 56 名患者中收集了总共 78 个 UL 和 34 个相邻的正常子宫肌层（NM）组织。该患者于 1995 年 10 月至 2004 年 2 月在巴西圣保罗马托格罗索州立大学博图卡图医学院的妇科接受治疗。
参与者/材料、地点和方法：从新鲜冷冻组织中评估基因表达谱，并与 exon 2 中的 MED12 突变进行比较。此外，应用 RT-qPCR 评估 HMGA2 及其预测的 miRNA 调节剂的表达水平：hsa-let-7a、miR-26a、miR-26b、mir-93 和 mir-106b。
无监督层次聚类分析显示出两个主要聚类，其中一个聚类（42 个 UL 中的 26 个）显示 MED12 突变病例丰富（26 个 UL 中的 18 个）。在两个聚类中均观察到 HMGA2 的表达水平增加，包括 MED12 突变的病例（聚类 1：18 UL）。与 NM 相比，在 UL 中发现 HMGA2 过表达（P < 0.001）。预测调节 HMGA2 的五个 miRNA 表达水平显著下调（P < 0.001），与 HMGA2 表达水平呈负相关（P < 0.05）。
局限性/谨慎的原因：由于技术限制，未进行体内功能研究来验证 microRNAs 和 HMGA2 相互作用。
在大量 MED12 突变的 UL 中检测到 HMGA2 过表达，表明这些改变共存。此外，描述了五个 microRNA 作为 UL 中 HMGA2 表达的潜在调节剂。
数据可在基因表达 Omnibus GSE42939 中获得。
本研究得到了巴西圣保罗州研究支持基金会（#2008/58835-2）和国家研究理事会（#485032/2007-4）的支持。作者声明没有利益冲突。
