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High Expression of IRS-1, RUNX3 and SMAD4 Are Positive Prognostic Factors in Stage I–III Colon Cancer

SIMPLE SUMMARY: We studied the expression of several protein biomarkers in both stromal and tumor tissue from colon cancer patients. High expression of IRS1 in stromal tissue and RUNX3 and SMAD4 in both stromal and tumor tissue were positive prognostic factors. Of particular interest, RUNX3 expressi...

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Autores principales: Selven, Hallgeir, Busund, Lill-Tove Rasmussen, Andersen, Sigve, Pedersen, Mona Irene, Lombardi, Ana Paola Giometti, Kilvaer, Thomas Karsten
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10000923/
https://www.ncbi.nlm.nih.gov/pubmed/36900240
http://dx.doi.org/10.3390/cancers15051448
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author Selven, Hallgeir
Busund, Lill-Tove Rasmussen
Andersen, Sigve
Pedersen, Mona Irene
Lombardi, Ana Paola Giometti
Kilvaer, Thomas Karsten
author_facet Selven, Hallgeir
Busund, Lill-Tove Rasmussen
Andersen, Sigve
Pedersen, Mona Irene
Lombardi, Ana Paola Giometti
Kilvaer, Thomas Karsten
author_sort Selven, Hallgeir
collection PubMed
description SIMPLE SUMMARY: We studied the expression of several protein biomarkers in both stromal and tumor tissue from colon cancer patients. High expression of IRS1 in stromal tissue and RUNX3 and SMAD4 in both stromal and tumor tissue were positive prognostic factors. Of particular interest, RUNX3 expression in stromal tissue was associated with the density of tumor-infiltrating lymphocytes. This finding may be important for understanding the prognostic impact of lymphocytes and predicting and increasing the efficacy of immunotherapy in colon cancer. ABSTRACT: Colon cancer is a common malignancy and a major contributor to human morbidity and mortality. In this study, we explore the expression and prognostic impact of IRS-1, IRS-2, RUNx3, and SMAD4 in colon cancer. Furthermore, we elucidate their correlations with miRs 126, 17-5p, and 20a-5p, which are identified as potential regulators of these proteins. Tumor tissue from 452 patients operated for stage I–III colon cancer was retrospectively collected and assembled into tissue microarrays. Biomarkers’ expressions were examined by immunohistochemistry and analyzed using digital pathology. In univariate analyses, high expression levels of IRS1 in stromal cytoplasm, RUNX3 in tumor (nucleus and cytoplasm) and stroma (nucleus and cytoplasm), and SMAD4 in tumor (nucleus and cytoplasm) and stromal cytoplasm were related to increased disease-specific survival (DSS). In multivariate analyses, high expression of IRS1 in stromal cytoplasm, RUNX3 in tumor nucleus and stromal cytoplasm, and high expression of SMAD4 in tumor and stromal cytoplasm remained independent predictors of improved DSS. Surprisingly, with the exception of weak correlations (0.2 < r < 0.25) between miR-126 and SMAD4, the investigated markers were mostly uncorrelated with the miRs. However, weak to moderate/strong correlations (0.3 < r < 0.6) were observed between CD3 and CD8 positive lymphocyte density and stromal RUNX3 expression. High expression levels of IRS1, RUNX3, and SMAD4 are positive prognostic factors in stage I–III colon cancer. Furthermore, stromal expression of RUNX3 is associated with increased lymphocyte density, suggesting that RUNX3 is an important mediator during recruitment and activation of immune cells in colon cancer.
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spelling pubmed-100009232023-03-11 High Expression of IRS-1, RUNX3 and SMAD4 Are Positive Prognostic Factors in Stage I–III Colon Cancer Selven, Hallgeir Busund, Lill-Tove Rasmussen Andersen, Sigve Pedersen, Mona Irene Lombardi, Ana Paola Giometti Kilvaer, Thomas Karsten Cancers (Basel) Article SIMPLE SUMMARY: We studied the expression of several protein biomarkers in both stromal and tumor tissue from colon cancer patients. High expression of IRS1 in stromal tissue and RUNX3 and SMAD4 in both stromal and tumor tissue were positive prognostic factors. Of particular interest, RUNX3 expression in stromal tissue was associated with the density of tumor-infiltrating lymphocytes. This finding may be important for understanding the prognostic impact of lymphocytes and predicting and increasing the efficacy of immunotherapy in colon cancer. ABSTRACT: Colon cancer is a common malignancy and a major contributor to human morbidity and mortality. In this study, we explore the expression and prognostic impact of IRS-1, IRS-2, RUNx3, and SMAD4 in colon cancer. Furthermore, we elucidate their correlations with miRs 126, 17-5p, and 20a-5p, which are identified as potential regulators of these proteins. Tumor tissue from 452 patients operated for stage I–III colon cancer was retrospectively collected and assembled into tissue microarrays. Biomarkers’ expressions were examined by immunohistochemistry and analyzed using digital pathology. In univariate analyses, high expression levels of IRS1 in stromal cytoplasm, RUNX3 in tumor (nucleus and cytoplasm) and stroma (nucleus and cytoplasm), and SMAD4 in tumor (nucleus and cytoplasm) and stromal cytoplasm were related to increased disease-specific survival (DSS). In multivariate analyses, high expression of IRS1 in stromal cytoplasm, RUNX3 in tumor nucleus and stromal cytoplasm, and high expression of SMAD4 in tumor and stromal cytoplasm remained independent predictors of improved DSS. Surprisingly, with the exception of weak correlations (0.2 < r < 0.25) between miR-126 and SMAD4, the investigated markers were mostly uncorrelated with the miRs. However, weak to moderate/strong correlations (0.3 < r < 0.6) were observed between CD3 and CD8 positive lymphocyte density and stromal RUNX3 expression. High expression levels of IRS1, RUNX3, and SMAD4 are positive prognostic factors in stage I–III colon cancer. Furthermore, stromal expression of RUNX3 is associated with increased lymphocyte density, suggesting that RUNX3 is an important mediator during recruitment and activation of immune cells in colon cancer. MDPI 2023-02-24 /pmc/articles/PMC10000923/ /pubmed/36900240 http://dx.doi.org/10.3390/cancers15051448 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Selven, Hallgeir
Busund, Lill-Tove Rasmussen
Andersen, Sigve
Pedersen, Mona Irene
Lombardi, Ana Paola Giometti
Kilvaer, Thomas Karsten
High Expression of IRS-1, RUNX3 and SMAD4 Are Positive Prognostic Factors in Stage I–III Colon Cancer
title High Expression of IRS-1, RUNX3 and SMAD4 Are Positive Prognostic Factors in Stage I–III Colon Cancer
title_full High Expression of IRS-1, RUNX3 and SMAD4 Are Positive Prognostic Factors in Stage I–III Colon Cancer
title_fullStr High Expression of IRS-1, RUNX3 and SMAD4 Are Positive Prognostic Factors in Stage I–III Colon Cancer
title_full_unstemmed High Expression of IRS-1, RUNX3 and SMAD4 Are Positive Prognostic Factors in Stage I–III Colon Cancer
title_short High Expression of IRS-1, RUNX3 and SMAD4 Are Positive Prognostic Factors in Stage I–III Colon Cancer
title_sort high expression of irs-1, runx3 and smad4 are positive prognostic factors in stage i–iii colon cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10000923/
https://www.ncbi.nlm.nih.gov/pubmed/36900240
http://dx.doi.org/10.3390/cancers15051448
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