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Journal of Gastroenterology

, Volume 53, Issue 8, pp 932–944 | Cite as

Insulin receptor substrate-4 is overexpressed in colorectal cancer and promotes retinoblastoma–cyclin-dependent kinase activation

  • Patricia Sanmartín-Salinas
  • María del Val Toledo Lobo
  • Fernando Noguerales-Fraguas
  • Miguel Toro Londoño
  • Antonio Jiménez-Ruiz
  • Luis Gonzalez Guijarro
Original Article—Alimentary Tract
  • 291 Downloads

Abstract

Background

Insulin receptor substrate 4 (IRS-4) is an adaptor protein for which new evidence suggests plays a role in tumour promotion.

Methods

We described nuclear IRS-4 in RKO colon cancer cell lines in biopsies of patients with colorectal cancer (CRC) (n = 20) and in matched adjacent normal colorectal (MANC) tissue (n = 20).

Results

Treatment with physiological doses of IGF-1 promoted nuclear influx of IRS-4 from cellular cytosol in RKO cells. When exogenous IRS-4 was overexpressed in RKO cells, there was an increase in cyclin D1, cyclin E, E2F1, pRB Ser 809/811 and pRB Ser 705 levels compared with the empty vector-transfected cells. Some of these changes returned to control values after wortmannin treatment. Subcellular fractionation showed an overexpression of IRS-4 in the cytoplasm, membrane, and nuclei of tumour samples, whereas the levels of the protein were barely detectable in the three compartments of normal samples. Immunohistochemical studies showed positive nuclear IRS-4 staining in over 74% of the tumour cells. IRS-4 was strongly overexpressed in tumoural tissues from CRC patients compared to MANC tissues. The up-regulation of IRS-4 in CRC samples correlated significantly with the increase of several G1 checkpoint proteins including cyclin D1 (r = 0.6662), Rb (r = 0.7779), pRb Serine 809/811 (r = 0.6864), pRb serine 705 (r = 0.6261) and E2F1 (r = 0.8702).

Conclusions

Taken together, our findings suggest that IRS-4 promotes retinoblastoma–cyclin-dependent kinase activation and it may serve as a pharmacological target since its expression is very low in normal tissue, including colonic epithelium.

Keywords

Nuclear IRS4 Cell proliferation Colorectal cancer Cell cycle IRS4 

Notes

Acknowledgements

This work was partially supported by the Spanish Grant S2010/BMD-2423 from Comunidad de Madrid. We gratefully acknowledge David Cano Martinez and Borja Hernandez Breijo for helpful discussions.

Compliance with ethical standards

Conflict of interest

The authors declare that they have not competing interest.

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Copyright information

© Japanese Society of Gastroenterology 2018

Authors and Affiliations

  • Patricia Sanmartín-Salinas
    • 1
  • María del Val Toledo Lobo
    • 2
  • Fernando Noguerales-Fraguas
    • 3
    • 4
  • Miguel Toro Londoño
    • 1
  • Antonio Jiménez-Ruiz
    • 1
  • Luis Gonzalez Guijarro
    • 1
    • 5
  1. 1.Department of System Biology,Unit of Biochemistry and Molecular BiologyUniversity of AlcaláAlcalá de HenaresSpain
  2. 2.Department of Biomedicine and Biotechnology,Unit of Cell BiologyUniversity of AlcaláAlcalá de HenaresSpain
  3. 3.Department of Surgery and Medical and Social SciencesUniversity of AlcaláAlcalá de HenaresSpain
  4. 4.Department of General SurgeryPríncipe de Asturias HospitalAlcalá de HenaresSpain
  5. 5.Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)BarcelonaSpain

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