MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1093/molehr/gay037 http://hdl.handle.net/11449/188270 |
Resumo: | 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. |
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MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyomaHMGA2 overexpressionMED12 mutationmicroRNAUterine leiomyomasSTUDY 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.CIPE-International Research Center AC Camargo Cancer CenterDepartment of Pathology and Laboratory Medicine Dartmouth-Hitchcock Medical CenterHermes Pardini Institute Research and Development DepartmentDepartment of Pathology School of Medicine University of Sao Paulo State - UNESPDepartment of Gynecology and Obstetrics School of Medicine University of Sao Paulo State - UNESPDepartment of Clinical Genetics Vejle Hospital Institute of Regional Health Research University of Southern DenmarkDepartment of Pathology School of Medicine University of Sao Paulo State - UNESPDepartment of Gynecology and Obstetrics School of Medicine University of Sao Paulo State - UNESPAC Camargo Cancer CenterDartmouth-Hitchcock Medical CenterResearch and Development DepartmentUniversidade Estadual Paulista (Unesp)University of Southern DenmarkMello, J. B.H.Barros-Filho, M. C.Abreu, F. B.Cirilo, P. D.R.Domingues, M. A.C. [UNESP]Pontes, A. [UNESP]Rogatto, S. R.2019-10-06T16:02:44Z2019-10-06T16:02:44Z2018-11-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article556-563http://dx.doi.org/10.1093/molehr/gay037Molecular Human Reproduction, v. 24, n. 11, p. 556-563, 2018.1460-24071360-9947http://hdl.handle.net/11449/18827010.1093/molehr/gay0372-s2.0-85055613186Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengMolecular Human Reproductioninfo:eu-repo/semantics/openAccess2021-10-22T22:23:58Zoai:repositorio.unesp.br:11449/188270Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462021-10-22T22:23:58Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma |
title |
MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma |
spellingShingle |
MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma Mello, J. B.H. HMGA2 overexpression MED12 mutation microRNA Uterine leiomyomas |
title_short |
MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma |
title_full |
MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma |
title_fullStr |
MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma |
title_full_unstemmed |
MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma |
title_sort |
MicroRNAs involved in the HMGA2 deregulation and its co-occurrence with MED12 mutation in uterine leiomyoma |
author |
Mello, J. B.H. |
author_facet |
Mello, J. B.H. Barros-Filho, M. C. Abreu, F. B. Cirilo, P. D.R. Domingues, M. A.C. [UNESP] Pontes, A. [UNESP] Rogatto, S. R. |
author_role |
author |
author2 |
Barros-Filho, M. C. Abreu, F. B. Cirilo, P. D.R. Domingues, M. A.C. [UNESP] Pontes, A. [UNESP] Rogatto, S. R. |
author2_role |
author author author author author author |
dc.contributor.none.fl_str_mv |
AC Camargo Cancer Center Dartmouth-Hitchcock Medical Center Research and Development Department Universidade Estadual Paulista (Unesp) University of Southern Denmark |
dc.contributor.author.fl_str_mv |
Mello, J. B.H. Barros-Filho, M. C. Abreu, F. B. Cirilo, P. D.R. Domingues, M. A.C. [UNESP] Pontes, A. [UNESP] Rogatto, S. R. |
dc.subject.por.fl_str_mv |
HMGA2 overexpression MED12 mutation microRNA Uterine leiomyomas |
topic |
HMGA2 overexpression MED12 mutation microRNA Uterine leiomyomas |
description |
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. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-11-01 2019-10-06T16:02:44Z 2019-10-06T16:02:44Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1093/molehr/gay037 Molecular Human Reproduction, v. 24, n. 11, p. 556-563, 2018. 1460-2407 1360-9947 http://hdl.handle.net/11449/188270 10.1093/molehr/gay037 2-s2.0-85055613186 |
url |
http://dx.doi.org/10.1093/molehr/gay037 http://hdl.handle.net/11449/188270 |
identifier_str_mv |
Molecular Human Reproduction, v. 24, n. 11, p. 556-563, 2018. 1460-2407 1360-9947 10.1093/molehr/gay037 2-s2.0-85055613186 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Molecular Human Reproduction |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
556-563 |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
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1797789461073887232 |