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RIZ2 at the crossroad of the EGF/EGFR signaling in colorectal cancer

BACKGROUND: Colorectal cancer (CRC) is the third most deadly and fourth most diagnosed cancer worldwide. Despite the progress in early diagnosis and advanced therapeutic options, CRC shows a poor prognosis with a 5 year survival rate of ~ 45%. PRDM2/RIZ, a member of PR/SET domain family (PRDM), expr...

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Autores principales: Di Donato, Marzia, Di Zazzo, Erika, Salvati, Annamaria, Sorrentino, Carmela, Giurato, Giorgio, Fiore, Donatella, Proto, Maria Chiara, Rienzo, Monica, Casamassimi, Amelia, Gazzerro, Patrizia, Bifulco, Maurizio, Castoria, Gabriella, Weisz, Alessandro, Nassa, Giovanni, Abbondanza, Ciro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10585774/
https://www.ncbi.nlm.nih.gov/pubmed/37853459
http://dx.doi.org/10.1186/s12967-023-04621-6
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author Di Donato, Marzia
Di Zazzo, Erika
Salvati, Annamaria
Sorrentino, Carmela
Giurato, Giorgio
Fiore, Donatella
Proto, Maria Chiara
Rienzo, Monica
Casamassimi, Amelia
Gazzerro, Patrizia
Bifulco, Maurizio
Castoria, Gabriella
Weisz, Alessandro
Nassa, Giovanni
Abbondanza, Ciro
author_facet Di Donato, Marzia
Di Zazzo, Erika
Salvati, Annamaria
Sorrentino, Carmela
Giurato, Giorgio
Fiore, Donatella
Proto, Maria Chiara
Rienzo, Monica
Casamassimi, Amelia
Gazzerro, Patrizia
Bifulco, Maurizio
Castoria, Gabriella
Weisz, Alessandro
Nassa, Giovanni
Abbondanza, Ciro
author_sort Di Donato, Marzia
collection PubMed
description BACKGROUND: Colorectal cancer (CRC) is the third most deadly and fourth most diagnosed cancer worldwide. Despite the progress in early diagnosis and advanced therapeutic options, CRC shows a poor prognosis with a 5 year survival rate of ~ 45%. PRDM2/RIZ, a member of PR/SET domain family (PRDM), expresses two main molecular variants, the PR-plus isoform (RIZ1) and the PR-minus (RIZ2). The imbalance in their expression levels in favor of RIZ2 is observed in many cancer types. The full length RIZ1 has been extensively investigated in several cancers where it acts as a tumor suppressor, whereas few studies have explored the RIZ2 oncogenic properties. PRDM2 is often target of frameshift mutations and aberrant DNA methylation in CRC. However, little is known about its role in CRC. METHODS: We combined in-silico investigation of The Cancer Genome Atlas (TCGA) CRC datasets, cellular and molecular assays, transcriptome sequencing and functional annotation analysis to assess the role of RIZ2 in human CRC. RESULTS: Our in-silico analysis on TCGA datasets confirmed that PRDM2 gene is frequently mutated and transcriptionally deregulated in CRC and revealed that a RIZ2 increase is highly correlated with a significant RIZ1 downregulation. Then, we assayed several CRC cell lines by qRT-PCR analysis for the main PRDM2 transcripts and selected DLD1 cell line, which showed the lowest RIZ2 levels. Therefore, we overexpressed RIZ2 in these cells to mimic TCGA datasets analysis results and consequently to assess the PRDM2/RIZ2 role in CRC. Data from RNA-seq disclosed that RIZ2 overexpression induced profound changes in CRC cell transcriptome via EGF pathway deregulation, suggesting that RIZ2 is involved in the EGF autocrine regulation of DLD1 cell behavior. Noteworthy, the forced RIZ2 expression increased cell viability, growth, colony formation, migration and organoid formation. These effects could be mediated by the release of high EGF levels by RIZ2 overexpressing DLD1 cells. CONCLUSIONS: Our findings add novel insights on the putative RIZ2 tumor-promoting functions in CRC, although additional efforts are warranted to define the underlying molecular mechanism. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04621-6.
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spelling pubmed-105857742023-10-20 RIZ2 at the crossroad of the EGF/EGFR signaling in colorectal cancer Di Donato, Marzia Di Zazzo, Erika Salvati, Annamaria Sorrentino, Carmela Giurato, Giorgio Fiore, Donatella Proto, Maria Chiara Rienzo, Monica Casamassimi, Amelia Gazzerro, Patrizia Bifulco, Maurizio Castoria, Gabriella Weisz, Alessandro Nassa, Giovanni Abbondanza, Ciro J Transl Med Research BACKGROUND: Colorectal cancer (CRC) is the third most deadly and fourth most diagnosed cancer worldwide. Despite the progress in early diagnosis and advanced therapeutic options, CRC shows a poor prognosis with a 5 year survival rate of ~ 45%. PRDM2/RIZ, a member of PR/SET domain family (PRDM), expresses two main molecular variants, the PR-plus isoform (RIZ1) and the PR-minus (RIZ2). The imbalance in their expression levels in favor of RIZ2 is observed in many cancer types. The full length RIZ1 has been extensively investigated in several cancers where it acts as a tumor suppressor, whereas few studies have explored the RIZ2 oncogenic properties. PRDM2 is often target of frameshift mutations and aberrant DNA methylation in CRC. However, little is known about its role in CRC. METHODS: We combined in-silico investigation of The Cancer Genome Atlas (TCGA) CRC datasets, cellular and molecular assays, transcriptome sequencing and functional annotation analysis to assess the role of RIZ2 in human CRC. RESULTS: Our in-silico analysis on TCGA datasets confirmed that PRDM2 gene is frequently mutated and transcriptionally deregulated in CRC and revealed that a RIZ2 increase is highly correlated with a significant RIZ1 downregulation. Then, we assayed several CRC cell lines by qRT-PCR analysis for the main PRDM2 transcripts and selected DLD1 cell line, which showed the lowest RIZ2 levels. Therefore, we overexpressed RIZ2 in these cells to mimic TCGA datasets analysis results and consequently to assess the PRDM2/RIZ2 role in CRC. Data from RNA-seq disclosed that RIZ2 overexpression induced profound changes in CRC cell transcriptome via EGF pathway deregulation, suggesting that RIZ2 is involved in the EGF autocrine regulation of DLD1 cell behavior. Noteworthy, the forced RIZ2 expression increased cell viability, growth, colony formation, migration and organoid formation. These effects could be mediated by the release of high EGF levels by RIZ2 overexpressing DLD1 cells. CONCLUSIONS: Our findings add novel insights on the putative RIZ2 tumor-promoting functions in CRC, although additional efforts are warranted to define the underlying molecular mechanism. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04621-6. BioMed Central 2023-10-18 /pmc/articles/PMC10585774/ /pubmed/37853459 http://dx.doi.org/10.1186/s12967-023-04621-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Di Donato, Marzia
Di Zazzo, Erika
Salvati, Annamaria
Sorrentino, Carmela
Giurato, Giorgio
Fiore, Donatella
Proto, Maria Chiara
Rienzo, Monica
Casamassimi, Amelia
Gazzerro, Patrizia
Bifulco, Maurizio
Castoria, Gabriella
Weisz, Alessandro
Nassa, Giovanni
Abbondanza, Ciro
RIZ2 at the crossroad of the EGF/EGFR signaling in colorectal cancer
title RIZ2 at the crossroad of the EGF/EGFR signaling in colorectal cancer
title_full RIZ2 at the crossroad of the EGF/EGFR signaling in colorectal cancer
title_fullStr RIZ2 at the crossroad of the EGF/EGFR signaling in colorectal cancer
title_full_unstemmed RIZ2 at the crossroad of the EGF/EGFR signaling in colorectal cancer
title_short RIZ2 at the crossroad of the EGF/EGFR signaling in colorectal cancer
title_sort riz2 at the crossroad of the egf/egfr signaling in colorectal cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10585774/
https://www.ncbi.nlm.nih.gov/pubmed/37853459
http://dx.doi.org/10.1186/s12967-023-04621-6
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