Insulin receptor substrate 1 may play divergent roles in human colorectal cancer development and progression

Abstract

BACKGROUND Despite effective prevention and screening methods, the incidence and mortality rates associated with colorectal cancer (CRC) are still high. 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 CRC biology and its value as a clinical CRC biomarker has not been well defined. AIM To evaluate 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. METHODS The expression of IRS-1, Bax, Bcl-xL and Ki-67 proteins was assessed in tissue samples obtained from 127 patients with primary CRC using immunohistochemical methods. The assays were performed using specific antibodies against IRS-1, Bax, Bcl-xL, Ki-67. The associations between the expression of IRS-1, Bax, Bcl-xL, Ki-67 were analyzed in relation to clinicopathological parameters, i.e. , patient age, sex, primary localization of tumor, histopathological type, grading, staging and lymph node spread. Correlations between variables were examined by Spearman rank correlation test and Fisher exact test with a level of significance at P < 0.05. RESULTS Immunohistochemical analysis of 127 CRC tissue samples 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 statistically significant correlations between expression of IRS-1 and both Bax and Bcl-xL in all CRC cases examined. The relationships between studied proteins were related to clinicopathological parameters of CRC. No significant correlation between the 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). CONCLUSION This study suggests that IRS-1 is co-expressed with both pro- and antiapoptotic markers and all these proteins are more prevalent in more differentiated CRC than in poorly differentiated CRC.

Prediction model of poorly differentiated colorectal cancer (CRC) based on gut bacteria

“…Liao et al [ 33 ] established a kNN classification model based on the clinicopathological information and protein expression profile analysis of CRC, which predicted the degree of tumor differentiation of CRC with high accuracy ( P ≤ 0.001, receiver-operator characteristics-ROC-error, 0.171). The expression of related genes, such as HER3 and insulin receptor substrate 1, was found to be a predictive target of the degree of CRC differentiation [ 34 , 35 ]. Metabolites from gut microbes also play an important role.…”

Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents

“…Nevertheless, it has been shown that IGF-1 receptor (IGF-1R) is overexpressed in CRC [28,46] and it is well established that the association of IGF-1 with its receptor stimulates cell proliferation and survival thus contributing to cancer development [28]. In addition, it was demonstrated that insulin receptor substrate-1, as the principal cellular effector of IGF-1R, is also overexpressed in CRC tissue [47,48], although a recent study by Lomperta et al [49] suggested a possibility of its divergent roles in the regulation of apoptosis. Furthermore, activation of the IGF-1/IGF-1R pathway can be at least partly responsible for CRC treatment resistance [28].…”

The Insulin Receptor Substrate 2 Mediates the Action of Insulin on HeLa Cell Migration via the PI3K/Akt Signaling Pathway

“…IRS-1 and IRS-2 are widely expressed in humans and are, therefore, the most studied proteins in the family [ 3 ]. There is a relationship between IRS-1 and 2 and various types of cancer, such as breast [ 4 , 5 , 6 , 7 , 8 ], lung [ 9 ], prostate [ 10 ], hepatocarcinoma [ 11 , 12 , 13 ], neuroblastoma [ 14 , 15 ], head and neck [ 16 ], colorectal [ 17 , 18 ], esophageal squamous cell carcinoma [ 19 ], non-small cell lung cancer [ 20 ], and glioblastoma multiforme [ 21 ]. It has been observed that the expression and function of the IRS may vary in the different types of cancer.…”