Retrospective Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2020; 26(28): 4140-4150
Published online Jul 28, 2020. doi: 10.3748/wjg.v26.i28.4140
Insulin receptor substrate 1 may play divergent roles in human colorectal cancer development and progression
Karolina Lomperta, Katarzyna Jakubowska, Malgorzata Grudzinska, Luiza Kanczuga-Koda, Andrzej Wincewicz, Eva Surmacz, Stanislaw Sulkowski, Mariusz Koda
Karolina Lomperta, Malgorzata Grudzinska, Stanislaw Sulkowski, Mariusz Koda, Department of General Pathomorphology, Medical University of Bialystok, Bialystok 15269, Poland
Katarzyna Jakubowska, Luiza Kanczuga-Koda, Department of Pathomorphology, Comprehensive Cancer Centre, Bialystok 15027, Poland
Andrzej Wincewicz, Department of Pathology, Nonpublic Health Care Unit, Kielce 25734, Poland
Eva Surmacz, Allysta Pharmaceuticals Incorporated, Belmont, CA 94002, United States
Author contributions: Lomperta K contributed to data analysis, literature review and writing the manuscript; Kanczuga-Koda L, Koda M and Wincewicz A contributed to data acquisition, data analysis and design of the manuscript; Jakubowska K and Grudzinska M contributed to literature review and manuscript drafting; Surmacz E contributed to editing the manuscript; Surmacz E, Sulkowski S and Koda M performed the revision and approval of the final version; Koda M supervised the project; all authors provided critical feedback and helped shape the research, analysis and manuscript.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of the Medical University of Bialystok, Poland.
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: All the Authors have no conflict of interest related to the manuscript.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Karolina Lomperta, MD, Doctor, Department of General Pathomorphology, Medical University of Bialystok, 13 Waszyngtona Street, Bialystok 15269, Poland. karlomperta@gmail.com
Received: April 30, 2020
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
Processing time: 88 Days and 20.8 Hours
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.

Keywords: Colorectal cancer; Insulin receptor substrate-1; Bax protein; Bcl-xL protein; Apoptosis; Antigen Ki-67

Core tip: We analyzed the expressions of Insulin receptor substrate 1 (IRS-1), Bax, Bcl-xL and Ki-67 proteins in primary colorectal cancer (CRC). We found that IRS-1 expression was associated with tumor grade and histological type, and was more prevalent in more differentiated CRC. Interestingly, IRS-1 expression was significantly correlated with Bax and Bcl-xL, but not with Ki-67. We hypothesize that coexpression of IRS-1 and proapoptotic and antiapoptotic markers could result in a complex and diverse interplay characteristic for earlier stages in CRC.