The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.

Colorectal cancer (CRC) is associated with lifestyle factors that affect insulin/IGF signaling, of which the insulin receptor substrate 1 (IRS1) is a key transducer. We investigated expression, localization and pathologic correlations of IRS1 in cancer-uninvolved colonic epithelium, primary CRCs wit...

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Autores principales:	Diana L Esposito, Federica Aru, Rossano Lattanzio, Annalisa Morgano, Michela Abbondanza, Reza Malekzadeh, Faraz Bishehsari, Rosa Valanzano, Antonio Russo, Mauro Piantelli, Antonio Moschetta, Lavinia Vittoria Lotti, Renato Mariani-Costantini
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/289c7a54eecd4ce7808739bc6bb5b28b
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spelling	oai:doaj.org-article:289c7a54eecd4ce7808739bc6bb5b28b2021-11-18T07:20:24ZThe insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.1932-620310.1371/journal.pone.0036190https://doaj.org/article/289c7a54eecd4ce7808739bc6bb5b28b2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22558377/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Colorectal cancer (CRC) is associated with lifestyle factors that affect insulin/IGF signaling, of which the insulin receptor substrate 1 (IRS1) is a key transducer. We investigated expression, localization and pathologic correlations of IRS1 in cancer-uninvolved colonic epithelium, primary CRCs with paired liver metastases and in vitro polarizing Caco2 and HT29 cells. IRS1 mRNA and protein resulted higher, relative to paired mucosa, in adenomas of familial adenomatous polyposis patients and in CRCs that overexpressed c-MYC, ß-catenin, InsRß, and IGF1R. Analysis of IRS1 immunostaining in 24 cases of primary CRC with paired colonic epithelium and hepatic metastasis showed that staining intensity was significantly higher in metastases relative to both primary CRC (P<0.01) and colonic epithelium (P<0.01). Primary and metastatic CRCs, compared to colonic epithelium, contained significantly higher numbers of IRS1-positive cells (P = 0.013 and P = 0.014, respectively). Pathologic correlations in 163 primary CRCs revealed that diffuse IRS1 staining was associated with tumors combining differentiated phenotype and aggressive markers (high Ki67, p53, and ß-catenin). In Caco 2 IRS1 and InsR were maximally expressed after polarization, while IGF1R was highest in pre-polarized cells. No nuclear IRS1 was detected, while, with polarization, phosphorylated IRS1 (pIRS1) shifted from the lateral to the apical plasma membrane and was expressed in surface cells only. In HT29, that carry mutations constitutively activating survival signaling, IRS1 and IGF1R decreased with polarization, while pIRS1 localized in nuclear spots throughout the course. Overall, these data provide evidence that IRS1 is modulated according to CRC differentiation, and support a role of IRS1 in CRC progression and liver metastatization.Diana L EspositoFederica AruRossano LattanzioAnnalisa MorganoMichela AbbondanzaReza MalekzadehFaraz BishehsariRosa ValanzanoAntonio RussoMauro PiantelliAntonio MoschettaLavinia Vittoria LottiRenato Mariani-CostantiniPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 4, p e36190 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Diana L Esposito Federica Aru Rossano Lattanzio Annalisa Morgano Michela Abbondanza Reza Malekzadeh Faraz Bishehsari Rosa Valanzano Antonio Russo Mauro Piantelli Antonio Moschetta Lavinia Vittoria Lotti Renato Mariani-Costantini The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.
description	Colorectal cancer (CRC) is associated with lifestyle factors that affect insulin/IGF signaling, of which the insulin receptor substrate 1 (IRS1) is a key transducer. We investigated expression, localization and pathologic correlations of IRS1 in cancer-uninvolved colonic epithelium, primary CRCs with paired liver metastases and in vitro polarizing Caco2 and HT29 cells. IRS1 mRNA and protein resulted higher, relative to paired mucosa, in adenomas of familial adenomatous polyposis patients and in CRCs that overexpressed c-MYC, ß-catenin, InsRß, and IGF1R. Analysis of IRS1 immunostaining in 24 cases of primary CRC with paired colonic epithelium and hepatic metastasis showed that staining intensity was significantly higher in metastases relative to both primary CRC (P<0.01) and colonic epithelium (P<0.01). Primary and metastatic CRCs, compared to colonic epithelium, contained significantly higher numbers of IRS1-positive cells (P = 0.013 and P = 0.014, respectively). Pathologic correlations in 163 primary CRCs revealed that diffuse IRS1 staining was associated with tumors combining differentiated phenotype and aggressive markers (high Ki67, p53, and ß-catenin). In Caco 2 IRS1 and InsR were maximally expressed after polarization, while IGF1R was highest in pre-polarized cells. No nuclear IRS1 was detected, while, with polarization, phosphorylated IRS1 (pIRS1) shifted from the lateral to the apical plasma membrane and was expressed in surface cells only. In HT29, that carry mutations constitutively activating survival signaling, IRS1 and IGF1R decreased with polarization, while pIRS1 localized in nuclear spots throughout the course. Overall, these data provide evidence that IRS1 is modulated according to CRC differentiation, and support a role of IRS1 in CRC progression and liver metastatization.
format	article
author	Diana L Esposito Federica Aru Rossano Lattanzio Annalisa Morgano Michela Abbondanza Reza Malekzadeh Faraz Bishehsari Rosa Valanzano Antonio Russo Mauro Piantelli Antonio Moschetta Lavinia Vittoria Lotti Renato Mariani-Costantini
author_facet	Diana L Esposito Federica Aru Rossano Lattanzio Annalisa Morgano Michela Abbondanza Reza Malekzadeh Faraz Bishehsari Rosa Valanzano Antonio Russo Mauro Piantelli Antonio Moschetta Lavinia Vittoria Lotti Renato Mariani-Costantini
author_sort	Diana L Esposito
title	The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.
title_short	The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.
title_full	The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.
title_fullStr	The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.
title_full_unstemmed	The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.
title_sort	insulin receptor substrate 1 (irs1) in intestinal epithelial differentiation and in colorectal cancer.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/289c7a54eecd4ce7808739bc6bb5b28b
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The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.

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