Published online Jul 28, 2020. doi: 10.3748/wjg.v26.i28.4140
Peer-review started: April 30, 2020
First decision: May 15, 2020
Revised: May 26, 2020
Accepted: July 17, 2020
Article in press: July 17, 2020
Published online: July 28, 2020
Insulin receptor substrate 1 (IRS-1), a signaling molecule involved in cell proliferation, survival and metabolic responses has been implicated in carcinogenic processes in various cellular and animal models. However, the role of IRS-1 in human colorectal cancer (CRC) biology and its value as a clinical CRC biomarker has not been well defined.
CRC is the third most common cancer diagnosed across the world. Despite effective prevention and screening methods CRC represents one of the most common causes of cancer-related deaths. Most of the research is aimed at finding new prognostic factors or therapeutic strategy in order to reduce high CRC-related mortality.
This study evaluated if and how IRS-1 expression and its associations with the apoptotic and proliferation tumor markers, Bax, Bcl-xL and Ki-67 are related to clinicopathological features in human CRC, i.e., patient age, sex, primary localization of tumor, histopathological type, grading, staging and lymph node spread.
We retrospectively collected data from 127 patients with primary CRC who underwent radical surgery with lymph node dissection. We analyzed the expressions of IRS-1, Bax, Bcl-xL and Ki-67 proteins using immunohistochemical methods. Correlations between variables were examined by Spearman rank correlation test and Fisher exact test with a level of significance at P < 0.05.
Immunohistochemical analysis revealed weak cytoplasmatic staining for IRS-1 in 66 CRC sections and strong cytoplasmatic staining in 61 cases. IRS-1 expression at any level in primary CRC was associated with tumor grade (69% in moderately differentiated tumors, G2 vs 31% in poorly differentiated tumors, G3) and with histological type (81.9% in adenocarcinoma vs 18.1% in adenocarcinoma with mucosal component cases). Strong IRS-1 positivity was observed more frequently in adenocarcinoma cases (95.1%) and in moderately differentiated tumors (85.2%). We also found different relationships between IRS-1 expression and both Bax and Bcl-xL proteins depended on clinicopathological parameters. Further analysis of the data revealed no significant correlation between expression of IRS-1 and proliferation marker Ki-67, excluding early stage tumors, where the correlation was positive and on a high level (P = 0.043, r = 0.723).
Our study adds to a growing corpus of research showing that (1) IRS-1 expression is more prevalent in more differentiated tumors, and our data indicate that (2) IRS-1 expression is correlated with both proapoptotic Bax and antiapoptotic Bcl-xL proteins.
Further research on this topic might extend the knowledge on the interactions and functional dependence between IRS-1 and apoptotic markers in CRC. In the future, the assessment of IRS-1 expression could be used to evaluate individual patient prognosis and might offer new insights into developing more efficient treatment strategies and identify patients who are most likely to respond to targeted therapies, for example the insulin-like growth factor 1 receptor inhibition.