Metallothionein expression in colorectal cancer: Relevance of different isoforms for tumor progression and patient survival

Autores
Arriaga, Juan Martín; Levy, Estrella Mariel; Bravo, Alicia Inés; Bayo, Sergio Morales; Amat, Mora; Aris, Mariana; Hannois, Adrián; Bruno, Luisina Inés; Roberti, Maria Paula; Sánchez Loria, Fernando; Pairola, Alejandro; Huertas, Eduardo; Mordoh, Jose; Bianchini, Michele
Año de publicación
2012
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Metallothioneins are a family of small, cysteine-rich proteins with many functions. Immunohistochemical evaluation of all metallothionein 1 + 2 isoforms in colorectal tumors has demonstrated an important down-regulation compared with normal tissue, although its prognostic significance is unclear. Moreover, the contribution of individual isoforms to overall metallothionein down-regulation is not known. To address these important issues, we analyzed the messenger RNA expression levels of all functional metallothionein 1 + 2 isoforms by quantitative reverse transcription polymerase chain reaction in 22 pairs of normal and tumor-microdissected epithelia and correlated these to the overall immunohistochemical protein expression. Our results showed that 5 isoforms (MT1G, 1E, 1F, 1H, and 1M) were lost during the transition from normal mucosa to tumor, whereas MT1X and MT2A were less down-regulated, and their expression was correlated with overall protein positivity. Second, we showed that MT1G hypermethylation occurred in cell lines and in 29% of tumor samples, whereas histone deacetylase inhibitors are able to induce most isoforms. Furthermore, we analyzed by immunohistochemistry 107 normal mucosae, 25 adenomas, 81 carcinomas, and 19 lymph node metastases to evaluate metallothionein expression during different stages of cancer development and to assess its relationship to patient survival. A lower immunohistochemical expression was associated with poorer survival, although it was not an independent predictor. Overall, this study identifies for the first time the relevant metallothionein isoforms for colorectal cancer progression, supports the concept that their loss is associated with worse prognosis, and suggests 2 mechanisms for epigenetic repression of metallothionein expression in colorectal tumors.
Fil: Arriaga, Juan Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Fil: Levy, Estrella Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Fil: Bravo, Alicia Inés. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; Argentina
Fil: Bayo, Sergio Morales. Municipio de Vicente López. Hospital Municipal "Prof. Dr Houssay"; Argentina
Fil: Amat, Mora. Instituto Médico Especializado "Alexander Fleming"; Argentina
Fil: Aris, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Hannois, Adrián. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; Argentina
Fil: Bruno, Luisina Inés. Instituto Médico Especializado "Alexander Fleming"; Argentina
Fil: Roberti, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Fil: Sánchez Loria, Fernando. Instituto Médico Especializado "Alexander Fleming"; Argentina
Fil: Pairola, Alejandro. Instituto Médico Especializado "Alexander Fleming"; Argentina
Fil: Huertas, Eduardo. Instituto Médico Especializado "Alexander Fleming"; Argentina
Fil: Mordoh, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Instituto Médico Especializado "Alexander Fleming"; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Fil: Bianchini, Michele. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Materia
Biomarker
Colorectal Cancer
Hypermethylation
Metallothioneins
Oncogenesis
Survival
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/59258
Acceder
id CONICETDig_f731ebc2df4a563346ce2b0c9e8977aa
oai_identifier_str oai:ri.conicet.gov.ar:11336/59258
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Metallothionein expression in colorectal cancer: Relevance of different isoforms for tumor progression and patient survivalArriaga, Juan MartínLevy, Estrella MarielBravo, Alicia InésBayo, Sergio MoralesAmat, MoraAris, MarianaHannois, AdriánBruno, Luisina InésRoberti, Maria PaulaSánchez Loria, FernandoPairola, AlejandroHuertas, EduardoMordoh, JoseBianchini, MicheleBiomarkerColorectal CancerHypermethylationMetallothioneinsOncogenesisSurvivalhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Metallothioneins are a family of small, cysteine-rich proteins with many functions. Immunohistochemical evaluation of all metallothionein 1 + 2 isoforms in colorectal tumors has demonstrated an important down-regulation compared with normal tissue, although its prognostic significance is unclear. Moreover, the contribution of individual isoforms to overall metallothionein down-regulation is not known. To address these important issues, we analyzed the messenger RNA expression levels of all functional metallothionein 1 + 2 isoforms by quantitative reverse transcription polymerase chain reaction in 22 pairs of normal and tumor-microdissected epithelia and correlated these to the overall immunohistochemical protein expression. Our results showed that 5 isoforms (MT1G, 1E, 1F, 1H, and 1M) were lost during the transition from normal mucosa to tumor, whereas MT1X and MT2A were less down-regulated, and their expression was correlated with overall protein positivity. Second, we showed that MT1G hypermethylation occurred in cell lines and in 29% of tumor samples, whereas histone deacetylase inhibitors are able to induce most isoforms. Furthermore, we analyzed by immunohistochemistry 107 normal mucosae, 25 adenomas, 81 carcinomas, and 19 lymph node metastases to evaluate metallothionein expression during different stages of cancer development and to assess its relationship to patient survival. A lower immunohistochemical expression was associated with poorer survival, although it was not an independent predictor. Overall, this study identifies for the first time the relevant metallothionein isoforms for colorectal cancer progression, supports the concept that their loss is associated with worse prognosis, and suggests 2 mechanisms for epigenetic repression of metallothionein expression in colorectal tumors.Fil: Arriaga, Juan Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Levy, Estrella Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Bravo, Alicia Inés. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Bayo, Sergio Morales. Municipio de Vicente López. Hospital Municipal "Prof. Dr Houssay"; ArgentinaFil: Amat, Mora. Instituto Médico Especializado "Alexander Fleming"; ArgentinaFil: Aris, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Hannois, Adrián. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; ArgentinaFil: Bruno, Luisina Inés. Instituto Médico Especializado "Alexander Fleming"; ArgentinaFil: Roberti, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Sánchez Loria, Fernando. Instituto Médico Especializado "Alexander Fleming"; ArgentinaFil: Pairola, Alejandro. Instituto Médico Especializado "Alexander Fleming"; ArgentinaFil: Huertas, Eduardo. Instituto Médico Especializado "Alexander Fleming"; ArgentinaFil: Mordoh, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Instituto Médico Especializado "Alexander Fleming"; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Bianchini, Michele. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaW B Saunders Co-Elsevier Inc2012-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/59258Arriaga, Juan Martín; Levy, Estrella Mariel; Bravo, Alicia Inés; Bayo, Sergio Morales; Amat, Mora; et al.; Metallothionein expression in colorectal cancer: Relevance of different isoforms for tumor progression and patient survival; W B Saunders Co-Elsevier Inc; Human Pathology; 43; 2; 2-2012; 197-2080046-8177CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0046817711001845info:eu-repo/semantics/altIdentifier/doi/10.1016/j.humpath.2011.04.015info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:59:53Zoai:ri.conicet.gov.ar:11336/59258instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:59:53.976CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Metallothionein expression in colorectal cancer: Relevance of different isoforms for tumor progression and patient survival
title Metallothionein expression in colorectal cancer: Relevance of different isoforms for tumor progression and patient survival
spellingShingle Metallothionein expression in colorectal cancer: Relevance of different isoforms for tumor progression and patient survival
Arriaga, Juan Martín
Biomarker
Colorectal Cancer
Hypermethylation
Metallothioneins
Oncogenesis
Survival
title_short Metallothionein expression in colorectal cancer: Relevance of different isoforms for tumor progression and patient survival
title_full Metallothionein expression in colorectal cancer: Relevance of different isoforms for tumor progression and patient survival
title_fullStr Metallothionein expression in colorectal cancer: Relevance of different isoforms for tumor progression and patient survival
title_full_unstemmed Metallothionein expression in colorectal cancer: Relevance of different isoforms for tumor progression and patient survival
title_sort Metallothionein expression in colorectal cancer: Relevance of different isoforms for tumor progression and patient survival
dc.creator.none.fl_str_mv Arriaga, Juan Martín
Levy, Estrella Mariel
Bravo, Alicia Inés
Bayo, Sergio Morales
Amat, Mora
Aris, Mariana
Hannois, Adrián
Bruno, Luisina Inés
Roberti, Maria Paula
Sánchez Loria, Fernando
Pairola, Alejandro
Huertas, Eduardo
Mordoh, Jose
Bianchini, Michele
author Arriaga, Juan Martín
author_facet Arriaga, Juan Martín
Levy, Estrella Mariel
Bravo, Alicia Inés
Bayo, Sergio Morales
Amat, Mora
Aris, Mariana
Hannois, Adrián
Bruno, Luisina Inés
Roberti, Maria Paula
Sánchez Loria, Fernando
Pairola, Alejandro
Huertas, Eduardo
Mordoh, Jose
Bianchini, Michele
author_role author
author2 Levy, Estrella Mariel
Bravo, Alicia Inés
Bayo, Sergio Morales
Amat, Mora
Aris, Mariana
Hannois, Adrián
Bruno, Luisina Inés
Roberti, Maria Paula
Sánchez Loria, Fernando
Pairola, Alejandro
Huertas, Eduardo
Mordoh, Jose
Bianchini, Michele
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Biomarker
Colorectal Cancer
Hypermethylation
Metallothioneins
Oncogenesis
Survival
topic Biomarker
Colorectal Cancer
Hypermethylation
Metallothioneins
Oncogenesis
Survival
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Metallothioneins are a family of small, cysteine-rich proteins with many functions. Immunohistochemical evaluation of all metallothionein 1 + 2 isoforms in colorectal tumors has demonstrated an important down-regulation compared with normal tissue, although its prognostic significance is unclear. Moreover, the contribution of individual isoforms to overall metallothionein down-regulation is not known. To address these important issues, we analyzed the messenger RNA expression levels of all functional metallothionein 1 + 2 isoforms by quantitative reverse transcription polymerase chain reaction in 22 pairs of normal and tumor-microdissected epithelia and correlated these to the overall immunohistochemical protein expression. Our results showed that 5 isoforms (MT1G, 1E, 1F, 1H, and 1M) were lost during the transition from normal mucosa to tumor, whereas MT1X and MT2A were less down-regulated, and their expression was correlated with overall protein positivity. Second, we showed that MT1G hypermethylation occurred in cell lines and in 29% of tumor samples, whereas histone deacetylase inhibitors are able to induce most isoforms. Furthermore, we analyzed by immunohistochemistry 107 normal mucosae, 25 adenomas, 81 carcinomas, and 19 lymph node metastases to evaluate metallothionein expression during different stages of cancer development and to assess its relationship to patient survival. A lower immunohistochemical expression was associated with poorer survival, although it was not an independent predictor. Overall, this study identifies for the first time the relevant metallothionein isoforms for colorectal cancer progression, supports the concept that their loss is associated with worse prognosis, and suggests 2 mechanisms for epigenetic repression of metallothionein expression in colorectal tumors.
Fil: Arriaga, Juan Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Fil: Levy, Estrella Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Fil: Bravo, Alicia Inés. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; Argentina
Fil: Bayo, Sergio Morales. Municipio de Vicente López. Hospital Municipal "Prof. Dr Houssay"; Argentina
Fil: Amat, Mora. Instituto Médico Especializado "Alexander Fleming"; Argentina
Fil: Aris, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Hannois, Adrián. Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal de Agudos "Eva Perón"; Argentina
Fil: Bruno, Luisina Inés. Instituto Médico Especializado "Alexander Fleming"; Argentina
Fil: Roberti, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Fil: Sánchez Loria, Fernando. Instituto Médico Especializado "Alexander Fleming"; Argentina
Fil: Pairola, Alejandro. Instituto Médico Especializado "Alexander Fleming"; Argentina
Fil: Huertas, Eduardo. Instituto Médico Especializado "Alexander Fleming"; Argentina
Fil: Mordoh, Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Instituto Médico Especializado "Alexander Fleming"; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Fil: Bianchini, Michele. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
description Metallothioneins are a family of small, cysteine-rich proteins with many functions. Immunohistochemical evaluation of all metallothionein 1 + 2 isoforms in colorectal tumors has demonstrated an important down-regulation compared with normal tissue, although its prognostic significance is unclear. Moreover, the contribution of individual isoforms to overall metallothionein down-regulation is not known. To address these important issues, we analyzed the messenger RNA expression levels of all functional metallothionein 1 + 2 isoforms by quantitative reverse transcription polymerase chain reaction in 22 pairs of normal and tumor-microdissected epithelia and correlated these to the overall immunohistochemical protein expression. Our results showed that 5 isoforms (MT1G, 1E, 1F, 1H, and 1M) were lost during the transition from normal mucosa to tumor, whereas MT1X and MT2A were less down-regulated, and their expression was correlated with overall protein positivity. Second, we showed that MT1G hypermethylation occurred in cell lines and in 29% of tumor samples, whereas histone deacetylase inhibitors are able to induce most isoforms. Furthermore, we analyzed by immunohistochemistry 107 normal mucosae, 25 adenomas, 81 carcinomas, and 19 lymph node metastases to evaluate metallothionein expression during different stages of cancer development and to assess its relationship to patient survival. A lower immunohistochemical expression was associated with poorer survival, although it was not an independent predictor. Overall, this study identifies for the first time the relevant metallothionein isoforms for colorectal cancer progression, supports the concept that their loss is associated with worse prognosis, and suggests 2 mechanisms for epigenetic repression of metallothionein expression in colorectal tumors.
publishDate 2012
dc.date.none.fl_str_mv 2012-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/59258
Arriaga, Juan Martín; Levy, Estrella Mariel; Bravo, Alicia Inés; Bayo, Sergio Morales; Amat, Mora; et al.; Metallothionein expression in colorectal cancer: Relevance of different isoforms for tumor progression and patient survival; W B Saunders Co-Elsevier Inc; Human Pathology; 43; 2; 2-2012; 197-208
0046-8177
CONICET Digital
CONICET
url http://hdl.handle.net/11336/59258
identifier_str_mv Arriaga, Juan Martín; Levy, Estrella Mariel; Bravo, Alicia Inés; Bayo, Sergio Morales; Amat, Mora; et al.; Metallothionein expression in colorectal cancer: Relevance of different isoforms for tumor progression and patient survival; W B Saunders Co-Elsevier Inc; Human Pathology; 43; 2; 2-2012; 197-208
0046-8177
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0046817711001845
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.humpath.2011.04.015
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv W B Saunders Co-Elsevier Inc
publisher.none.fl_str_mv W B Saunders Co-Elsevier Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842269608472477696
score 13.13397

Publicaciones similares