The insulin receptor substrate 1 (irs1) in intestinal epithelial differentiation and in colorectal cancer

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

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere36190
JournalPLoS One
Volume7
Issue number4
DOIs
StatePublished - Apr 27 2012

Fingerprint

Insulin Receptor Substrate Proteins
colorectal neoplasms
Colorectal Neoplasms
epithelium
Epithelium
metastasis
Catenins
Polarization
Neoplasm Metastasis
Liver
liver
insulin receptors
cells
Staining and Labeling
HT29 Cells
Adenomatous Polyposis Coli
neoplasms
adenoma
Cell membranes
Liver Neoplasms

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Esposito, D. L., Aru, F., Lattanzio, R., Morgano, A., Abbondanza, M., Malekzadeh, R., ... Mariani-Costantini, R. (2012). The insulin receptor substrate 1 (irs1) in intestinal epithelial differentiation and in colorectal cancer. PLoS One, 7(4), [e36190]. https://doi.org/10.1371/journal.pone.0036190

The insulin receptor substrate 1 (irs1) in intestinal epithelial differentiation and in colorectal cancer. / Esposito, Diana L.; Aru, Federica; Lattanzio, Rossano; Morgano, Annalisa; Abbondanza, Michela; Malekzadeh, Reza; Bishehsari, Faraz; Valanzano, Rosa; Russo, Antonio; Piantelli, Mauro; Moschetta, Antonio; Lotti, Lavinia Vittoria; Mariani-Costantini, Renato.

In: PLoS One, Vol. 7, No. 4, e36190, 27.04.2012.

Research output: Contribution to journalArticle

Esposito, DL, Aru, F, Lattanzio, R, Morgano, A, Abbondanza, M, Malekzadeh, R, Bishehsari, F, Valanzano, R, Russo, A, Piantelli, M, Moschetta, A, Lotti, LV & Mariani-Costantini, R 2012, 'The insulin receptor substrate 1 (irs1) in intestinal epithelial differentiation and in colorectal cancer', PLoS One, vol. 7, no. 4, e36190. https://doi.org/10.1371/journal.pone.0036190
Esposito DL, Aru F, Lattanzio R, Morgano A, Abbondanza M, Malekzadeh R et al. The insulin receptor substrate 1 (irs1) in intestinal epithelial differentiation and in colorectal cancer. PLoS One. 2012 Apr 27;7(4). e36190. https://doi.org/10.1371/journal.pone.0036190
Esposito, Diana L. ; Aru, Federica ; Lattanzio, Rossano ; Morgano, Annalisa ; Abbondanza, Michela ; Malekzadeh, Reza ; Bishehsari, Faraz ; Valanzano, Rosa ; Russo, Antonio ; Piantelli, Mauro ; Moschetta, Antonio ; Lotti, Lavinia Vittoria ; Mariani-Costantini, Renato. / The insulin receptor substrate 1 (irs1) in intestinal epithelial differentiation and in colorectal cancer. In: PLoS One. 2012 ; Vol. 7, No. 4.
@article{a5e933dae4984cc1a328157c76538988,
title = "The insulin receptor substrate 1 (irs1) in intestinal epithelial differentiation and in colorectal cancer",
abstract = "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, InsR{\ss}, 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.",
author = "Esposito, {Diana L.} and Federica Aru and Rossano Lattanzio and Annalisa Morgano and Michela Abbondanza and Reza Malekzadeh and Faraz Bishehsari and Rosa Valanzano and Antonio Russo and Mauro Piantelli and Antonio Moschetta and Lotti, {Lavinia Vittoria} and Renato Mariani-Costantini",
year = "2012",
month = "4",
day = "27",
doi = "10.1371/journal.pone.0036190",
language = "English (US)",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - The insulin receptor substrate 1 (irs1) in intestinal epithelial differentiation and in colorectal cancer

AU - Esposito, Diana L.

AU - Aru, Federica

AU - Lattanzio, Rossano

AU - Morgano, Annalisa

AU - Abbondanza, Michela

AU - Malekzadeh, Reza

AU - Bishehsari, Faraz

AU - Valanzano, Rosa

AU - Russo, Antonio

AU - Piantelli, Mauro

AU - Moschetta, Antonio

AU - Lotti, Lavinia Vittoria

AU - Mariani-Costantini, Renato

PY - 2012/4/27

Y1 - 2012/4/27

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84860491023&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860491023&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0036190

DO - 10.1371/journal.pone.0036190

M3 - Article

C2 - 22558377

AN - SCOPUS:84860491023

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

M1 - e36190

ER -