Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development
Abstract Background Cancer cells are characterized by chromosomal instability (CIN) and it is thought that errors in pathways involved in faithful chromosome segregation play a pivotal role in the genesis of CIN. Cohesin forms a large protein ring that binds DNA strands by encircling them. In additi...
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doaj-0414178f31f14431b00819e5f7abf6df2020-11-25T03:01:00ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-03-0138111610.1186/s13046-019-1116-0Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer developmentPatrizia Sarogni0Orazio Palumbo1Adele Servadio2Simonetta Astigiano3Barbara D’Alessio4Veronica Gatti5Dubravka Cukrov6Silvia Baldari7Maria Michela Pallotta8Paolo Aretini9Felice Dell’Orletta10Silvia Soddu11Massimo Carella12Gabriele Toietta13Ottavia Barbieri14Gabriella Fontanini15Antonio Musio16Institute for Genetic and Biomedical Research (IRGB), National Research Council (CNR)Division of Medical Genetics, IRCCS “Casa Sollievo della Sofferenza”Division of Pathology, Department of Surgery, University of PisaIRCCS Ospedale Policlinico San Martino, Department of Translational OncologyInstitute for Genetic and Biomedical Research (IRGB), National Research Council (CNR)IRCCS Regina Elena National Cancer Institute, Department of Research, Advanced Diagnostic and Technological InnovationInstitute for Genetic and Biomedical Research (IRGB), National Research Council (CNR)IRCCS Regina Elena National Cancer Institute, Department of Research, Advanced Diagnostic and Technological InnovationInstitute for Genetic and Biomedical Research (IRGB), National Research Council (CNR)Fondazione Pisana per la Scienza ONLUSInstitute for Computational Linguistics (ILC) “A. Zampolli”, National Research Council (CNR)IRCCS Regina Elena National Cancer Institute, Department of Research, Advanced Diagnostic and Technological InnovationDivision of Medical Genetics, IRCCS “Casa Sollievo della Sofferenza”IRCCS Regina Elena National Cancer Institute, Department of Research, Advanced Diagnostic and Technological InnovationDepartment of Experimental Medicine, University of GenoaDivision of Pathology, Department of Surgery, University of PisaInstitute for Genetic and Biomedical Research (IRGB), National Research Council (CNR)Abstract Background Cancer cells are characterized by chromosomal instability (CIN) and it is thought that errors in pathways involved in faithful chromosome segregation play a pivotal role in the genesis of CIN. Cohesin forms a large protein ring that binds DNA strands by encircling them. In addition to this central role in chromosome segregation, cohesin is also needed for DNA repair, gene transcription regulation and chromatin architecture. Though mutations in both cohesin and cohesin-regulator genes have been identified in many human cancers, the contribution of cohesin to cancer development is still under debate. Methods Normal mucosa, early adenoma, and carcinoma samples deriving from 16 subjects affected by colorectal cancer (CRC) were analyzed by OncoScan for scoring both chromosome gains and losses (CNVs) and loss of heterozygosity (LOH). Then the expression of SMC1A was analyzed by immunochemistry in 66 subjects affected by CRC. The effects of SMC1A overexpression and mutated SMC1A were analyzed in vivo using immunocompromised mouse models. Finally, we measured global gene expression profiles in induced-tumors by RNA-seq. Results Here we showed that SMC1A cohesin core gene was present as extra-copies, mutated, and overexpressed in human colorectal carcinomas. We then demonstrated that cohesin overexpression led to the development of aggressive cancers in immunocompromised mice through gene expression dysregulation. Conclusion Collectively, these results support a role of defective cohesin in the development of human colorectal cancer.http://link.springer.com/article/10.1186/s13046-019-1116-0CohesinSMC1AChromosome instabilityGene expression dysregulationHuman colorectal cancer development |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Patrizia Sarogni Orazio Palumbo Adele Servadio Simonetta Astigiano Barbara D’Alessio Veronica Gatti Dubravka Cukrov Silvia Baldari Maria Michela Pallotta Paolo Aretini Felice Dell’Orletta Silvia Soddu Massimo Carella Gabriele Toietta Ottavia Barbieri Gabriella Fontanini Antonio Musio |
spellingShingle |
Patrizia Sarogni Orazio Palumbo Adele Servadio Simonetta Astigiano Barbara D’Alessio Veronica Gatti Dubravka Cukrov Silvia Baldari Maria Michela Pallotta Paolo Aretini Felice Dell’Orletta Silvia Soddu Massimo Carella Gabriele Toietta Ottavia Barbieri Gabriella Fontanini Antonio Musio Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development Journal of Experimental & Clinical Cancer Research Cohesin SMC1A Chromosome instability Gene expression dysregulation Human colorectal cancer development |
author_facet |
Patrizia Sarogni Orazio Palumbo Adele Servadio Simonetta Astigiano Barbara D’Alessio Veronica Gatti Dubravka Cukrov Silvia Baldari Maria Michela Pallotta Paolo Aretini Felice Dell’Orletta Silvia Soddu Massimo Carella Gabriele Toietta Ottavia Barbieri Gabriella Fontanini Antonio Musio |
author_sort |
Patrizia Sarogni |
title |
Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development |
title_short |
Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development |
title_full |
Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development |
title_fullStr |
Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development |
title_full_unstemmed |
Overexpression of the cohesin-core subunit SMC1A contributes to colorectal cancer development |
title_sort |
overexpression of the cohesin-core subunit smc1a contributes to colorectal cancer development |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2019-03-01 |
description |
Abstract Background Cancer cells are characterized by chromosomal instability (CIN) and it is thought that errors in pathways involved in faithful chromosome segregation play a pivotal role in the genesis of CIN. Cohesin forms a large protein ring that binds DNA strands by encircling them. In addition to this central role in chromosome segregation, cohesin is also needed for DNA repair, gene transcription regulation and chromatin architecture. Though mutations in both cohesin and cohesin-regulator genes have been identified in many human cancers, the contribution of cohesin to cancer development is still under debate. Methods Normal mucosa, early adenoma, and carcinoma samples deriving from 16 subjects affected by colorectal cancer (CRC) were analyzed by OncoScan for scoring both chromosome gains and losses (CNVs) and loss of heterozygosity (LOH). Then the expression of SMC1A was analyzed by immunochemistry in 66 subjects affected by CRC. The effects of SMC1A overexpression and mutated SMC1A were analyzed in vivo using immunocompromised mouse models. Finally, we measured global gene expression profiles in induced-tumors by RNA-seq. Results Here we showed that SMC1A cohesin core gene was present as extra-copies, mutated, and overexpressed in human colorectal carcinomas. We then demonstrated that cohesin overexpression led to the development of aggressive cancers in immunocompromised mice through gene expression dysregulation. Conclusion Collectively, these results support a role of defective cohesin in the development of human colorectal cancer. |
topic |
Cohesin SMC1A Chromosome instability Gene expression dysregulation Human colorectal cancer development |
url |
http://link.springer.com/article/10.1186/s13046-019-1116-0 |
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