Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Feb 15, 2025; 17(2): 98808
Published online Feb 15, 2025. doi: 10.4251/wjgo.v17.i2.98808
Identifying adipocyte-derived exosomal miRNAs as potential novel prognostic markers for radiotherapy of esophageal squamous cell carcinoma
Yang-Yang Ge, Xiao-Chun Xia, An-Qing Wu, Chen-Ying Ma, Ling-Hui Yu, Ju-Ying Zhou
Yang-Yang Ge, Chen-Ying Ma, Ju-Ying Zhou, Department of Radiation Oncology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
Yang-Yang Ge, Xiao-Chun Xia, Department of Radiotherapy, The Affiliated Tumor Hospital of Nantong University, Nantong 226361, Jiangsu Province, China
An-Qing Wu, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, Jiangsu Province, China
Ling-Hui Yu, Department of Brachytherapy, The Affiliated Tumor Hospital of Nantong University, Nantong 226361, Jiangsu Province, China
Co-first authors: Yang-Yang Ge and Xiao-Chun Xia.
Co-corresponding authors: Ling-Hui Yu and Ju-Ying Zhou.
Author contributions: Ge YY and Xia XC conceptualized and designed the research; Yu LH and Zhou JY screened patients and acquired clinical data; Wu AQ and Ma CY collected blood specimen and performed laboratory analysis; Ge YY and Xia XC performed data analysis and basic experiments; Ge YY and Xia XC wrote the paper. All the authors have read and approved the final manuscript. Ge YY proposed, designed and conducted serum exosomes analysis, performed data analysis and prepared the first draft of the manuscript. Xia XC was responsible for patient screening, enrollment, collection of clinical data and analysis. Both authors have made crucial and indispensable contributions towards the completion of the project and thus qualified as the co-first authors of the paper. Both Yu LH and Zhou JY have played important and indispensable roles in the experimental design, data interpretation and manuscript preparation as the co-corresponding authors. Zhou JY applied for and obtained the funds for this research project. Yu LH conceptualized, designed, and supervised the whole process of the project. He searched the literature, revised and submitted the early version of the manuscript. Zhou JY was instrumental and responsible for data re-analysis and re-interpretation, figure plotting, comprehensive literature search, preparation and submission of the current version of the manuscript. This collaboration between Zhou JY and Yu LH is crucial for the publication of this manuscript and other manuscripts still in preparation.
Supported by the National Natural Science Foundation of China, No. 81602792 and No. 12205215; and Science and Technology Program of Nantong, No. JC12022103.
Institutional review board statement: In accordance with the Declaration of Helsinki and the relevant regulations of the Ministry of Health on the "Measures for Ethical Review of Biomedical Research Involving Human Beings (for Trial Implementation)" (2007), the Research Ethics Committee of the Institute held a project review meeting in the afternoon of February 10, 2022 to review the project, No. 2022-014-001.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The data used to support the findings of this study are available upon request at zhoujuyingsy@163.com.
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: Ju-Ying Zhou, FAASLD, MD, Department of Radiation Oncology, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, Suzhou 215006, Jiangsu Province, China. zhoujuyingsy@163.com
Received: July 6, 2024
Revised: October 27, 2024
Accepted: November 14, 2024
Published online: February 15, 2025
Processing time: 196 Days and 1.7 Hours
Abstract
BACKGROUND

Radiation resistance limits radiotherapy efficacy in esophageal squamous cell carcinoma (ESCC). The tumor microenvironment, particularly adipocytes, plays a role in promoting cancer progression. Extracellular vesicles and microRNAs (miRNAs) regulate gene expression and hold prognostic potential for esophageal carcinoma. Elucidating radioresistance mechanisms and identifying radiosensitization targets can help enhance radiotherapy efficacy for esophageal cancer.

AIM

To investigate the potential role of miRNAs derived from adipocyte exosomes as prognostic markers for radiotherapy efficacy in ESCC.

METHODS

Free adipocytes were isolated from human thoracic adipose tissue. A co-culture model of adipocytes and ESCC cells was established to observe colony formation and cell survival post-irradiation. ESCC cell apoptosis was assessed by flow cytometry. Western Blot and immunofluorescence assays were performed to evaluate DNA damage in ESCC cells post-irradiation. Adipocyte-derived exosomes were isolated by ultracentrifugation and identified by electron microscopy. A similar set of experiments was performed on ESCC cells to analyze cell survival, apoptosis, and DNA damage post-radiation exposure. Exosomes from adipose tissue and serum exosomes from ESCC patients pre- and post-radiotherapy were subjected to high-throughput miRNA-sequencing and validated using real-time quantitative polymerase chain reaction. The correlation between potential target miRNAs and the short-term prognosis of radiotherapy in ESCC was evaluated by receiver operating characteristic curve analysis.

RESULTS

Co-culturing adipocytes with ESCC cells enhanced radioresistance, as evidenced by increased colony formation. Adipocyte co-culture reduced ESCC cell apoptosis and DNA damage post-radiation. Adipocyte-derived exosomes similarly conferred radioresistance in ESCC cells, decreasing apoptosis and DNA damage post-irradiation. High-throughput miRNA-sequencing identified miR-660-5p in serum and adipose tissue exosomes. Patients with high expression of serum exosome miR-660-5p showed poor prognosis after radiotherapy.

CONCLUSION

Adipocyte-derived exosomal miR-660-5p is a potential biomarker for evaluating radiotherapy efficacy in ESCC.

Keywords: Esophageal squamous cell carcinoma; Adipocyte; Exosomes; MicroRNA; Radiotherapy

Core Tip: This study revealed for the first time the impact of adipocyte-derived extracellular vesicle microRNAs on the radiosensitivity of esophageal squamous cell carcinoma (ESCC), providing valuable resources for studying the tumor microenvironment and ESCC, as well as predicting patient responses to radiotherapy.