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MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma.
Mol Hum Reprod. 2018 11 01; 24(11):556-563.MH

Abstract

STUDY QUESTION

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)?

SUMMARY ANSWER

The co-occurrence of MED12 mutation and HMGA2 overexpression, and a negative correlation of five validated or predicted microRNAs that target HMGA2 were reported.

WHAT IS KNOWN ALREADY

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.

MAIN RESULTS AND THE ROLE OF CHANCE

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.

LIMITATIONS REASONS FOR CAUTION

An in vivo functional study was not performed to validate the microRNAs and HMGA2 interaction due to technical limitations.

WIDER IMPLICATIONS OF THE FINDINGS

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.

Authors+Show Affiliations

CIPE-International Research Center-AC Camargo Cancer Center, Sao Paulo, SP, Brazil.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.Hermes Pardini Institute, Research & Development Department, Belo Horizonte, MG, Brazil.Department of Pathology, School of Medicine, University of Sao Paulo State-UNESP, Botucatu-SP, Brazil.Department of Gynecology and Obstetrics, School of Medicine, University of Sao Paulo State-UNESP, Botucatu-SP, Brazil.Department of Clinical Genetics, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, DK, Denmark.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30376129

Citation

Mello, J B H., et al. "MicroRNAs Involved in the HMGA2 Deregulation and Its Co-occurrence With MED12 Mutation in Uterine Leiomyoma." Molecular Human Reproduction, vol. 24, no. 11, 2018, pp. 556-563.
Mello JBH, Barros-Filho MC, Abreu FB, et al. MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma. Mol Hum Reprod. 2018;24(11):556-563.
Mello, J. B. H., Barros-Filho, M. C., Abreu, F. B., Cirilo, P. D. R., Domingues, M. A. C., Pontes, A., & Rogatto, S. R. (2018). MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma. Molecular Human Reproduction, 24(11), 556-563. https://doi.org/10.1093/molehr/gay037
Mello JBH, et al. MicroRNAs Involved in the HMGA2 Deregulation and Its Co-occurrence With MED12 Mutation in Uterine Leiomyoma. Mol Hum Reprod. 2018 11 1;24(11):556-563. PubMed PMID: 30376129.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma. AU - Mello,J B H, AU - Barros-Filho,M C, AU - Abreu,F B, AU - Cirilo,P D R, AU - Domingues,M A C, AU - Pontes,A, AU - Rogatto,S R, PY - 2018/04/04/received PY - 2018/08/21/accepted PY - 2018/10/31/entrez PY - 2018/10/31/pubmed PY - 2019/8/14/medline SP - 556 EP - 563 JF - Molecular human reproduction JO - Mol. Hum. Reprod. VL - 24 IS - 11 N2 - STUDY QUESTION: 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)? SUMMARY ANSWER: The co-occurrence of MED12 mutation and HMGA2 overexpression, and a negative correlation of five validated or predicted microRNAs that target HMGA2 were reported. WHAT IS KNOWN ALREADY: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LIMITATIONS REASONS FOR CAUTION: An in vivo functional study was not performed to validate the microRNAs and HMGA2 interaction due to technical limitations. WIDER IMPLICATIONS OF THE FINDINGS: 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. SN - 1460-2407 UR - https://www.unboundmedicine.com/medline/citation/30376129/MicroRNAs_involved_in_the_HMGA2_deregulation_and_its_co_occurrence_with_MED12_mutation_in_uterine_leiomyoma_ L2 - https://academic.oup.com/molehr/article-lookup/doi/10.1093/molehr/gay037 DB - PRIME DP - Unbound Medicine ER -