Wu J, Guo Y, Zuo ZF, Zhu ZW, Han L. MMP14 is a diagnostic gene of intrahepatic cholangiocarcinoma associated with immune cell infiltration. World J Gastroenterol 2023; 29(19): 2961-2978 [PMID: 37274806 DOI: 10.3748/wjg.v29.i19.2961]
Corresponding Author of This Article
Lei Han, MD, Associate Chief Physician, Deputy Director, Department of Hepatobiliary Surgery, The General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenyang 110016, Liaoning Province, China. hanlei1974@sina.com
Research Domain of This Article
Oncology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
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: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. May 21, 2023; 29(19): 2961-2978 Published online May 21, 2023. doi: 10.3748/wjg.v29.i19.2961
MMP14 is a diagnostic gene of intrahepatic cholangiocarcinoma associated with immune cell infiltration
Jun Wu, Yang Guo, Zhi-Fan Zuo, Zi-Wei Zhu, Lei Han
Jun Wu, Zi-Wei Zhu, China Medical University, The General Hospital of Northern Theater Command Training Base for Graduate, Shenyang 110016, Liaoning Province, China
Yang Guo, Lei Han, Department of Hepatobiliary Surgery, The General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
Zhi-Fan Zuo, Gynecological Radiotherapy Ward, Liaoning Provincial Cancer Hospital, Shenyang 110801, Liaoning province, China
Author contributions: Han L conceived and directed the entire study, and should be regarded as corresponding author; Wu J and Guo Y designed the study and prepared the manuscript; Zuo ZF defined the intellectual content of the study and participated in the literature research; Wu J, Guo Y, and Zuo ZF contributed equally to this study; Zhu ZW conducted data analysis; Han L and Wu J revised the manuscript; and all authors approved to submit the manuscript.
Institutional review board statement: This study is not involved any human and animal.
Conflict-of-interest statement: The authors declare no conflict of interest.
Data sharing statement: The bioinformatic data could be downloaded from the public databases, and 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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Lei Han, MD, Associate Chief Physician, Deputy Director, Department of Hepatobiliary Surgery, The General Hospital of Northern Theater Command, No. 83 Wenhua Road, Shenyang 110016, Liaoning Province, China. hanlei1974@sina.com
Received: February 28, 2023 Peer-review started: February 28, 2023 First decision: March 14, 2023 Revised: March 24, 2023 Accepted: April 23, 2023 Article in press: April 23, 2023 Published online: May 21, 2023
Abstract
BACKGROUND
Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor of the hepatobiliary system with concealed onset, strong invasiveness and poor prognosis.
AIM
To explore the disease characteristic genes that may be helpful in the diagnosis of ICC and affect immune cell infiltration.
METHODS
We downloaded two ICC-related human gene expression profiles from GEO database as the training group (GSE26566 and GSE32958 datasets) for difference analysis, and performed enrichment analysis on differential genes. The least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF), three machine learning algorithms, were used to screen the characteristic genes. Double verification was carried out on GSE107943 and The Cancer Genome Atlas, two verification groups. Receiver operating characteristic curve and area under the curve (AUC) were used to evaluate the diagnostic efficacy of genes for ICC. CIBERSORT and ssGSEA algorithms were used to evaluate the effect of characteristic genes on immune infiltration pattern. Human Protein Atlas (HPA) was used to analyze the protein expression level of the target gene.
RESULTS
A total of 1091 differential genes were obtained in the training group. Enrichment analysis showed that the above genes were mainly enriched in small molecular catabolism, complement and coagulation cascade, bile secretion and other functions and pathways. Twenty-five characteristic genes were screened by LASSO regression, 19 by SVM-RFE algorithm, and 30 by RF algorithm. Three algorithms were used in combination to determine the characteristic gene of ICC: MMP14. The verification group confirmed that the genes had a high diagnostic accuracy (AUC values of the training group and the verification group were 0.960, 0.999, and 0.977, respectively). Comprehensive analysis of immune infiltration showed that MMP14 could affect the infiltration of monocytes, activated memory CD4 T cells, resting memory CD4 T cells, and other immune cells, and was closely related to the expression of CD200, cytotoxic T-lymphocyte-associated antigen 4, CD14, CD44, and other immune checkpoints. The results of immunohistochemistry in HPA database showed was indeed overexpressed in ICC.
CONCLUSION
MMP14 can be used as a disease characteristic gene of ICC, and may regulate the distribution of immune-infiltrating cells in the ICC tumor microenvironment, which provides a new method for the determination of ICC diagnostic markers and screening of therapeutic targets.
Core Tip: This study demonstrates that a new candidate molecular marker: MMP14 that is important for the diagnosis of intrahepatic cholangiocarcinoma, and MMP14 was related to a variety of immune cell components and participated in the occurrence and development in intrahepatic cholangiocarcinoma.
