Clinical Trials Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 14, 2023; 29(26): 4200-4213
Published online Jul 14, 2023. doi: 10.3748/wjg.v29.i26.4200
Raf kinase inhibitor protein combined with phosphorylated extracellular signal-regulated kinase offers valuable prognosis in gastrointestinal stromal tumor
Wen-Zhi Qu, Luan Wang, Juan-Juan Chen, Yang Wang
Wen-Zhi Qu, Yang Wang, Department of General Surgery, The 4th Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
Luan Wang, Department of Emergency, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
Juan-Juan Chen, Department of Medical Service, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
Author contributions: Wang Y designed research; Wang Y, Wang L and Qu WZ performed research; Wang Y and Qu WZ analyzed data; Wang Y, Chen JJ and Wang L wrote the paper; Wang Y edited the paper and provided primary revised opinion; All authors have read and approve the final manuscript.
Supported by Natural Science Foundation of Liaoning Province, No.2020-MS-148.
Institutional review board statement: The study was reviewed and approved by the 4th Affiliated Hospital of China Medical University’s Institutional Review Board, No. EC-2020-KS-015.
Informed consent statement: Consent was not obtained but the presented data are anonymized, and risk of identification is low. With the approval of the ethics committee, informed consent was waived.
Conflict-of-interest statement: The authors report grants from Natural Science Foundation of Liaoning Province, China, during the conduct of the study. We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted and entitled 'Raf kinase inhibitor protein combined with phosphorylated extracellular signal-regulated kinase offers valuable prognosis in gastrointestinal stromal tumor'.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at wwyy840731@126.com. Consent was not obtained but the presented data are anonymized, and risk of identification is low. No additional data are available.
CONSORT 2010 statement: The authors have read the CONSORT 2010 statement, and the manuscript was prepared and revised according to the CONSORT 2010 statement.
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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yang Wang, MD, PhD, Associate Professor, Doctor, Department of General Surgery, The 4th Affiliated Hospital of China Medical University, No. 4 Chongshan Road, Huanggu District, Shenyang 110032, Liaoning Province, China. wwyy840731@126.com
Received: April 24, 2023
Peer-review started: April 24, 2023
First decision: May 16, 2023
Revised: May 20, 2023
Accepted: June 2, 2023
Article in press: June 2, 2023
Published online: July 14, 2023
Processing time: 77 Days and 1 Hours
Abstract
BACKGROUND

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Tyrosine kinase inhibitors, such as imatinib, have been used as first-line therapy for the treatment of GISTs. Although these drugs have achieved considerable efficacy in some patients, reports of resistance and recurrence have emerged. Extracellular signal-regulated kinase 1/2 (ERK1/2) protein, as a member of the mitogen-activated protein kinase (MAPK) family, is a core molecule of this signaling pathway. Nowadays, research reports on the important clinical and prognostic value of phosphorylated-ERK (P-ERK) and phosphorylated-MAPK/ERK kinase (P-MEK) proteins closely related to raf kinase inhibitor protein (RKIP) have gradually emerged in digestive tract tumors such as gastric cancer, colon cancer, and pancreatic cancer. However, literature on the expression of these downstream proteins combined with RKIP in GIST is scarce. This study will focus on this aspect and search for answers to the problem.

AIM

To detect the expression of RKIP, P-ERK, and P-MEK protein in GIST and to analyze their relationship with clinicopathological characteristics and prognosis of this disease. Try to establish a new prognosis evaluation model using RKIP and P-ERK in combination with analysis and its prognosis evaluation efficacy.

METHODS

The research object of our experiment was 66 pathologically diagnosed GIST patients with complete clinical and follow-up information. These patients received surgical treatment at China Medical University Affiliated Hospital from January 2015 to January 2020. Immunohistochemical method was used to detect the expression of RKIP, P-ERK, and P-MEK proteins in GIST tissue samples from these patients. Kaplan-Meier method was used to calculate the survival rate of 63 patients with complete follow-up data. A Nomogram was used to represent the new prognostic evaluation model. The Cox multivariate regression analysis was conducted separately for each set of risk evaluation factors, based on two risk classification systems [the new risk grade model vs the modified National Institutes of Health (NIH) 2008 risk classification system]. Receiver operating characteristic (ROC) curves were used for evaluating the accuracy and efficiency of the two prognostic evaluation systems.

RESULTS

In GIST tissues, RKIP protein showed positive expression in the cytoplasm and cell membrane, appearing as brownish-yellow or brown granules. The expression of RKIP was related to GIST tumor size, NIH grade, and mucosal invasion. P-ERK protein exhibited heterogeneous distribution in GIST cells, mainly in the cytoplasm, with occasional presence in the nucleus, and appeared as brownish-yellow granules, and the expression of P-ERK protein was associated with GIST tumor size, mitotic count, mucosal invasion, and NIH grade. Meanwhile, RKIP protein expression was negatively correlated with P-ERK expression. The results in COX multivariate regression analysis showed that RKIP protein expression was not an independent risk factor for tumor prognosis. However, RKIP combined with P-ERK protein expression were identified as independent risk factors for prognosis with statistical significance. Furthermore, we establish a new prognosis evaluation model using RKIP and P-ERK in combination and obtained the nomogram of the new prognosis evaluation model. ROC curve analysis also showed that the new evaluation model had better prognostic performance than the modified NIH 2008 risk classification system.

CONCLUSION

Our experimental results showed that the expression of RKIP and P-ERK proteins in GIST was associated with tumor size, NIH 2008 staging, and tumor invasion, and P-ERK expression was also related to mitotic count. The expression of the two proteins had a certain negative correlation. The combined expression of RKIP and P-ERK proteins can serve as an independent risk factor for predicting the prognosis of GIST patients. The new risk assessment model incorporating RKIP and P-ERK has superior evaluation efficacy and is worth further practical application to validate.

Keywords: Raf kinase inhibitory protein; Phosphorylated extracellular-signal-regulated kinase; Gastrointestinal stromal tumors; Immunohistochemistry; Survival analysis; Risk grade model

Core Tip: Nowadays, research reports on the expression of downstream proteins of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase pathway combined with raf kinase inhibitor protein (RKIP) in gastrointestinal stromal tumor (GIST) is scarce. This study will focus on this aspect and use immunohistochemistry methods, large sample survival analysis data, and the latest bioinformatics analysis techniques to answer the problem. Our experimental results showed that the expression of the two proteins had a certain negative correlation. The combined expression of RKIP and phosphorylated-ERK proteins can serve as an independent risk factor for predicting the prognosis of GIST patients. Furthermore, the new risk assessment model incorporating RKIP and phosphorylated-ERK has superior evaluation efficacy.