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.
ABSTRACT
In many types of cancer, microRNAs (miRs) are aberrantly expressed. The aim of this study was to explore the prognostic impact of miR-17-5p and miR-20a-5p in colon cancer. Tumor tissue from 452 stage I-III colon cancer patients was retrospectively collected and tissue microarrays constructed. miR-17-5p and miR-20a-5p expression was evaluated by in situ hybridization and analyzed using digital pathology. Cell line experiments, using HT-29 and CACO-2, were performed to assess the effect of miR-17-5p and miR-20a-5p over expression on viability, invasion and migration. In multivariate analyses, high miR-17-5p expression in tumor (HR = 0.43, CI 0.26-0.71, p < 0.001) and high expression of miR-20a-5p in tumor (HR = 0.60, CI 0.37-0.97, p = 0.037) and stroma (HR = 0.63, CI 0.42-0.95, p = 0.027) remained independent predictors of improved disease-specific survival. In cell lines, over expression of both miRs resulted in mitigated migration without any significant effect on viability or invasion. In conclusion, in stage I-III colon cancer, high expression of both miR-17-5p and miR-20a-5p are independent predictors of favorable prognosis.
