Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jul 15, 2023; 15(7): 1182-1199
Published online Jul 15, 2023. doi: 10.4251/wjgo.v15.i7.1182
ENTPD1-AS1–miR-144-3p-mediated high expression of COL5A2 correlates with poor prognosis and macrophage infiltration in gastric cancer
Han-Mei Yuan, Xiao-Feng Pu, Hui Wu, Chao Wu
Han-Mei Yuan, Hui Wu, Chao Wu, Department of Laboratory Medicine, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
Xiao-Feng Pu, Department of Clinical Laboratory, The General Hospital of Western Theater Command, Chengdu 610000, Sichuan Province, China
Author contributions: Yuan HM designed the experiments and wrote the manuscript; Pu XF and Wu H collected clinical specimens and completed the related experiments; Wu C reviewed and edited the manuscript; All authors contributed to the article and approved the submitted version.
Supported by National Natural Science Foundation of China, No. 81971489; and Natural Science Foundation of Guangdong Province, No. 2022A1515011122.
Institutional review board statement: The study was reviewed and approved by the Medical Research Ethics Committee of the Eighth Affiliated Hospital of Sun Yat-sen University, No. ZB-KYIRB-AF/SC-08/01.0.
Informed consent statement: All study participants or their legal guardian provided informed written consent about personal and medical data collection prior to study enrolment.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.
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: Chao Wu, PhD, Professor, Department of Laboratory Medicine, The Eighth Affiliated Hospital, Sun Yat-sen University, No. 3025 Shennan Zhong Lu, Shenzhen 518033, Guangdong Province, China. chaowu261@163.com
Received: December 7, 2022
Peer-review started: December 7, 2022
First decision: January 18, 2023
Revised: March 30, 2023
Accepted: April 30, 2023
Article in press: April 30, 2023
Published online: July 15, 2023
Processing time: 217 Days and 1.5 Hours
Abstract
BACKGROUND

Gastric cancer (GC) is a malignant tumor with high morbidity and mortality. Expression of COL5A2 is significantly elevated in GC. Abnormal expression of noncoding RNAs (ncRNAs) have been found in GC, including microRNA (miRNA) and long noncoding RNA (lncRNA). Competing endogenous RNA network plays an important regulatory role in GC. However, its specific regulatory mechanism has not been elucidated.

AIM

To gain insight into the ncRNA regulatory mechanism and immune microenvironment related to COL5A2 in GC.

METHODS

RNA sequencing data and clinical information from The Cancer Genome Atlas data portal were used to analyze the expressions of COL5A2, miRNA and lncRNA related to the prognosis of GC. Cox regression analysis and Kyoto Encyclopedia of Genes and Genomes analysis were performed to assess the risk factors and relevant function of COL5A2. StarBase was used to predict the interaction of miRNA–lncRNA or miRNA–mRNA in GC. The relationship between COL5A2, miR-144-3p and ENTPD1-AS1 were verified by dual luciferase reporter assay. The association of COL5A2 with immune cell infiltration were analyzed using the Tumor Immune Estimation Resource database and single sample gene set enrichment analysis. The expression of COL5A2 and macrophages in paired GC tissues were detected by immunohistochemical staining.

RESULTS

We verified that the upregulation of COL5A2 expression was associated with the prognosis of GC and was an independent risk factor for GC. miR-144-3p was downregulated and correlated with the prognosis of GC. miR-144-3p regulated the expression of COL5A2 through direct interaction with COL5A2. ENTPD1-AS1 was elevated in GC and competitively bound to miR-144-3p, thus inhibiting the expression of miR-144-3p. ENTPD1-AS1 enhanced the expression of COL5A2 through sponging miR-144-3p. Compared to paired normal tissue, COL5A2 expression was upregulated at the protein level, especially in the middle and late stages of GC. The high expression of COL5A2 was positively linked to macrophage infiltration in GC.

CONCLUSION

COL5A2 regulated by ENTPD1-AS1–miR-144-3p was associated with poor prognosis and macrophage infiltration in GC. This could be a new biomarker and therapeutic target in GC.

Keywords: COL5A2; Noncoding RNAs; Macrophage infiltration; Prognosis; Gastric cancer

Core Tip: Gastric cancer (GC) is a malignant tumor with high fatality rate. Competing endogenous RNA network and infiltration of immune cells play an important role in the development of GC. In this study, we verified that high expression of COL5A2 was closely related to poor prognosis and was an independent risk factor for GC. We predicted and validated that long noncoding RNA ENTPD1-AS1 regulated the expression of COL5A2 through sponging miR-144-3p. Additionally, we confirmed that upregulation of COL5A2 expression strongly correlated with immune infiltration of macrophages. ENTPD1-AS1-miR-144-3p-COL5A2 might be a new therapeutic target for GC.