Clinical Trials Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 21, 2018; 24(23): 2508-2517
Published online Jun 21, 2018. doi: 10.3748/wjg.v24.i23.2508
Clinical and prognostic significance of Raf kinase inhibitory protein expression in gastrointestinal stromal tumors
Yang Wang, Juan-Juan Chen, Xiao-Fei Wang, Qiang Wang
Yang Wang, Juan-Juan Chen, Xiao-Fei Wang, Qiang Wang, Department of Gastrointestinal Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
Author contributions: Wang Y designed research; Wang Y performed research; Wang Y and Chen JJ contributed new reagents or analytic tools; Wang Y and Wang XF analyzed data; Wang Y wrote the paper; Wang Q edited the paper and provided primary revised opinion.
Institutional review board statement: The study was reviewed and approved by Sheng-Jing Hospital of China Medical University Institutional Review Board.
Informed consent statement: The patient involved in this study gave her written informed consent authorizing use and disclosure of her protected health information.
Conflict-of-interest statement: All the authors have no conflicts of interests to declare.
CONSORT 2010 statement: the guidelines of the CONSORT 2010 Statement have been adopted.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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:
Correspondence to: Qiang Wang, PhD, Doctor, Professor, Department of Gastrointestinal Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China.
Telephone: +86-24-96615
Received: March 14, 2018
Peer-review started: March 14, 2018
First decision: March 30, 2018
Revised: April 5, 2018
Accepted: April 26, 2018
Article in press: April 26, 2018
Published online: June 21, 2018
Research background

Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal mesenchymal tumor. Raf kinase inhibitory protein (RKIP) protein is both a kinase inhibitor and a phosphorylation target. It has important and complex functions in regulating tumor growth, metastasis, cell cycle, and apoptosis. Many recent articles on RKIP proteins have reported a link to various cancers, including gastric cancer, bowel cancer, esophageal cancer, and gynecologic oncology. However, there are only a few references on the expression of RKIP protein in gastrointestinal stromal tumors.

Research motivation

The following problems, which we need to solve urgently, are also the research motivation of this article: (1) The function of the RKIP in the GISTs neoplastic generation and metastasis; (2) the relationship between the RKIP expression and GIST clinical data; and (3) the relationship between the prognosis of GIST and RKIP.

Research objectives

In this study, we examined the expression of RKIP in GISTs by immunohistochemistry to explore the clinical significance of GIST expression and its prognosis. This research will provide evidence and support for the diagnosis of GIST, prognostic evaluation, and new tumor treatment targets

Research methods

The study included 63 cases of paraffin-embedded specimens of surgically resected and pathologically confirmed clinical specimens from Shengjing Hospital Affiliated to China Medical University. All the cases are clinically and pathologically complete, dated from January 2011 to January 2015. The expression of RKIP protein was analyzed by immunohistochemistry. The Kaplan-Meier method was used to calculate the overall survival of 60 patients followed up for survival analysis. The prognostic significance of each index was analyzed by COX multiple regression to clarify further the value of RKIP protein level in the diagnosis and prognosis of GISTs.

Research results

In GIST tissues, RKIP protein was positively expressed in the cytoplasm and cell membrane with brownish-yellow or brown granules. RKIP protein positive expression was found in 34 (54%) of the 63 specimens in this experiment, and the total negative expression was 29 (46%). The RKIP positive expression was related with GIST tumor size, NIH grade, and mucosal invasion. RKIP and age, gender, tumor location, and how many mitotic figures were not related. Kaplan-Meier method was used to draw the survival curves related to RKIP differential expression. The results showed that the 1, 3, and 5-year survival rates of RKIP positive group were 94.4%, 89.2% and 80.5%, respectively. The survival rates of RKIP negative group at 1, 3, and 5 years were only 88.6%, 68.2%, and 48.2%, respectively. Comparing with the RKIP negative Group, the RKIP high expression group was correlated with a better survival rate (Log-Rank analysis, P = 0.0015). The results of the COX multivariate analysis showed that the prognosis of patients with GISTs was related to NIH grade (P = 0.037) and Exp (B) was 3.664, indicating that NIH risk grade was an important factor to evaluate the prognosis of patients. However, the expression of RKIP correlated with the prognosis of patients (P = 0.122). The Exp (B) value was 2.855, suggesting that RKIP expression may have some reference value for the survival of GIST.

Research conclusions

The expression of RKIP protein in GISTs correlated with tumor size, NIH stage, and invasiveness of the mucosa (invasion degree), and each index suggested that the higher the degree of malignancy was associated with lower or more loss of RKIP expression. When compared with other factors (age, sex, tumor location, etc.), there was no relationship with RKIP level. RKIP overexpression was positively correlated with the survival of patients with GISTs, which has some implications for the prognosis of patients. RKIP expression has certain reference value for the survival of GIST, but it cannot be used as an independent factor to evaluate the prognosis of GISTs.

Research perspectives

As a complex protein, RKIP has a “multi-directional switch” function on many cell conduction pathways. RKIP remains a hot topic in recent cancer research. However, data on the relationship between RKIP and the pathogenesis and treatment of GIST still remains unclear. Additional studies on the mechanisms underlying RKIP expression disorder will possibly find that RKIP protein is marker protein for prognostication of GIST. In addition to its potential as a monitoring indicator, regulation and target treatment of RKIP could be a treatment option for GIST. Thus, RKIP may have practical value in understanding the biological characteristics and expression of GIST.