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©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Pathological significance of abnormal recepteur d’origine nantais and programmed death ligand 1 expression in colorectal cancer
Yi-Zhi Liu, Da-Ting Han, Dan-Rong Shi, Bo Hong, Yun Qian, Zhi-Gang Wu, Shu-Hao Yao, Tao-Ming Tang, Ming-Hai Wang, Xiang-Ming Xu, Hang-Ping Yao
Yi-Zhi Liu, Da-Ting Han, Dan-Rong Shi, Zhi-Gang Wu, Tao-Ming Tang, Hang-Ping Yao, Department of Cancer Biology Research, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
Bo Hong, Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
Yun Qian, Department of Clinical Laboratory, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
Shu-Hao Yao, Department of Stomatology, Wenzhou Medical University Renji College, Wenzhou 325035, Zhejiang Province, China
Ming-Hai Wang, Cancer Biology Research Center and Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, United States
Xiang-Ming Xu, Department of Cancer Biology Research, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
Author contributions: Yao HP, Xu XM, and Wang MH carried out the experimental design and supervision; Yao HP, Liu YZ, Hong B, Qian Y, Tang TM, Wu ZG, Yao SH, and Xu XM conducted the sample collection, immunohistochemistry, and multiplex immunofluorescence analysis; Liu YZ, Shi DR, and Han DT performed the in vitro cellular experiments and data analysis; Yao HP, Wang MH, and Liu YZ drafted the manuscript; all authors read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81872883 (to Yao HP); Zhejiang Major Medical Health & Sciences Technology Foundation Projects, No. WKJ-ZJ-13 (to Yao HP); and Zhejiang Provincial Natural Science Foundation of China, No. LY18H160014 (to Xu XM).
Institutional review board statement: The study was reviewed and approved by the First Affiliated Hospital, Zhejiang University School of Medicine (reference number: 2017427-1).
Conflict-of-interest statement: The authors confirm that there are no known conflicts of interest associated with this publication. The manuscript has been read and approved by all authors and there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of authors.
Data sharing statement: All data generated or analyzed during this study are included in the published paper. More details can be provided on request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Hang-Ping Yao, PhD, Professor, Department of Cancer Biology Research, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China.
yaohangping@zju.edu.cn
Received: August 9, 2020
Peer-review started: August 9, 2020
First decision: August 22, 2020
Revised: September 6, 2020
Accepted: September 18, 2020
Article in press: September 18, 2020
Published online: November 15, 2020
Processing time: 94 Days and 12 Hours
BACKGROUND
Programmed death ligand 1 (PD-L1) immunotherapy remains poorly efficacious in colorectal cancer (CRC). The recepteur d’origine nantais (RON) receptor tyrosine kinase plays an important role in regulating tumor immunity.
AIM
To identify the patterns of RON and PD-L1 expression and explore their clinical significance in CRC.
METHODS
Gene expression data from the Gene Expression Omnibus database (GEO; n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine (FAHZUSM; n = 381) were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor microenvironment of CRC. HT29 cell line was treated with BMS-777607 to explore the relationship between RON activity and PD-L1 expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and Western blot.
RESULTS
In the GEO patient cohort, cut-off values for RON and PD-L1 expression were determined to be 7.70 and 4.3, respectively. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 was associated with a poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121 (32%), 43 (11%), 91 (24%), and 51 (13.4%), respectively. High expression of RON was significantly correlated with high expression of PD-L1 in the tumor cell compartment (P < 0.001). High expression of RON and that of PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with a poor prognosis. In vitro, BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in CRC cells.
CONCLUSION
RON, PD-L1, and their crosstalk are significant in predicting the prognostic value of CRC. Moreover, phosphorylation of RON upregulates PD-L1 expression, which provides a novel approach to immunotherapy in CRC.
Core Tip: Recepteur d’origine nantais (RON) expression plays an important role in regulating tumor immunity, and the efficacy of programmed death ligand 1 (PD-L1) immunotherapy in colorectal cancer (CRC) is still not satisfactory. This inspired us to study the clinical significance and correlation of RON and PD-L1 in CRC. The major discoveries and findings in this study are: (1) The abnormal expression of RON and PD-L1 was not only correlated, but was also significant biomarkers for poor prognosis of CRC. This finding was identified in 389 primary CRC clinical samples via multiplex immunofluorescence staining and immunohistochemistry staining; and (2) In in vitro experiments, activation of RON phosphorylation up-regulated the expression of PD-L1 in CRC cells.
