Clinical and Translational Research
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 14, 2021; 27(30): 5076-5087
Published online Aug 14, 2021. doi: 10.3748/wjg.v27.i30.5076
Association of gene and protein expression and genetic polymorphism of CC chemokine ligand 4 in colorectal cancer
Levar Shamoun, Kalle Landerholm, Amanda Balboa Ramilo, Roland E Andersson, Jan Dimberg, Dick Wågsäter
Levar Shamoun, Amanda Balboa Ramilo, Dick Wågsäter, Department of Medical Cell Biology, Uppsala University, Uppsala 75123, Sweden
Levar Shamoun, Department of Laboratory Medicine and Pathology, Region Jönköping County, Jönköping 55305, Sweden
Kalle Landerholm, Roland E Andersson, Department of Surgery, Region Jönköping County, Jönköping 55305, Sweden
Kalle Landerholm, Roland E Andersson, Department of Biomedical and Clinical Science, Linköping University, Linköping 58185, Sweden
Jan Dimberg, Department of Natural Science and Biomedicine, School of Health and Welfare, Jönköping University, Jönköping 55111, Sweden
Author contributions: Dimberg J and Wågsäter D designed and coordinated the study; Shamoun L and Balboa-Ramilo A performed the experiments, acquired and analyzed data; Shamoun L, Balboa-Ramilo A, Landerholm K, Andersson RE, Dimberg J, and Wågsäter D interpreted the data; Landerholm K and Andersson RE recruited the patients; Shamoun L, Dimberg J, and Wågsäter D wrote the manuscript; All authors made critical revisions of the manuscript and approved the final version of the article.
Supported by Medical Research Council of Southeast Sweden (FORSS) and Division of Medical Diagnostics (Futurum), Region Jönköping County, Sweden.
Institutional review board statement: The investigation was approved by the Regional Ethical Review Board in Linköping, Linköping, Sweden and informed consent was obtained from each of the participants.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare no conflicts of interest.
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: Dick Wågsäter, PhD, Professor, Department of Medical Cell Biology, Uppsala University, Husargatan 3, Uppsala 75237, Sweden. dick.wagsater@mcb.uu.se
Received: March 31, 2021
Peer-review started: March 31, 2021
First decision: May 28, 2021
Revised: June 7, 2021
Accepted: July 13, 2021
Article in press: July 13, 2021
Published online: August 14, 2021
Processing time: 131 Days and 18.7 Hours
Abstract
BACKGROUND

Leukocytes, such as T cells and macrophages, play an important role in tumorigenesis. CC chemokine ligand (CCL) 4, which is produced by lymphocytes and macrophages, has been found to be expressed in the mucosa of the gastrointestinal tract and is a potent chemoattractant for various leukocytes.

AIM

To examine CCL4 expression and its genetic polymorphism rs10491121 in patients with colorectal cancer (CRC) and evaluate their prognostic significance.

METHODS

Luminex technology was used to determine CCL4 Levels in CRC tissue (n = 98), compared with paired normal tissue, and in plasma from patients with CRC (n = 103), compared with healthy controls (n = 97). Included patients had undergone surgical resection for primary colorectal adenocarcinomas between 1996 and 2019 at the Department of Surgery, Ryhov County Hospital, Jönköping, Sweden. Reverse transcription quantitative PCR was used to investigate the CCL4 gene expression in CRC tissue (n = 101). Paired normal tissue and TaqMan single nucleotide polymorphism assays were used for the CCL4 rs10491121 polymorphism in 610 CRC patients and 409 healthy controls.

RESULTS

The CCL4 protein and messenger RNA expression levels were higher in CRC tissue than in normal paired tissue (90%, P < 0.001 and 45%, P < 0.05, respectively). CRC tissue from patients with localized disease had 2.8-fold higher protein expression levels than that from patients with disseminated disease. Low CCL4 protein expression levels in CRC tissue were associated with a 30% lower cancer-specific survival rate in patients (P < 0.01). The level of plasma CCL4 was 11% higher in CRC patients than in healthy controls (P < 0.05) and was positively correlated (r = 0.56, P < 0.01) with the CCL4 protein level in CRC tissue. The analysis of CCL4 gene polymorphism rs10491121 showed a difference (P < 0.05) between localized disease and disseminated disease in the right colon, with a dominance of allele A in localized disease. Moreover, the rate of the A allele was higher among CRC patients with mucinous cancer than among those with non-mucinous cancer.

CONCLUSION

The present study indicates that the CRC tissue levels of CCL4 and CCL4 gene polymorphism rs10491121, particularly in the right colon, are associated with clinical outcome in CRC patients.

Keywords: CC chemokine ligand 4; Gene polymorphism; Gene and protein expression; Chemokine; Survival rate; Colorectal cancer

Core Tip: Our data suggest that the CC chemokine ligand (CCL) 4 rs10491121 polymorphism is associated with colorectal cancer (CRC), particularly mucinous CRC and CRC in the right colon. Moreover, we observed that CCL4 protein expression was upregulated in CRC tissues compared with in normal tissues, was correlated with disease stage and that low expression was related to a 30% lower cancer-specific survival rate.