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

RUNX transcription factors: biological functions and implications in cancer

“…Ning et al disclosed that reduced JMJD1A expression in gastric cancer is associated with invasive phenotypes and poor prognosis, and this association is further substantiated by a positive correlation between JMJD1A and RUNX3 expression, indicating that reduced RUNX3 expression serves as an indicator of unfavorable prognosis [ 93 ]. In colon cancer, increased RUNX3 expression levels in tumor epithelial cells and stromal cells are independent predictors of a good prognosis [ 120 ]. Complementing these findings, Zhang et al confirmed that decreased expression of RUNX3 in CRC tissues and cells is linked to poor prognosis, accentuating its function as a tumor suppressor [ 94 ].…”