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©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Quantitative proteomics analysis reveals the pathogenesis of obstructed defecation syndrome caused by abnormal expression of dystrophin
Wen-Zhe Li, Yu Xiong, Tian-Kun Wang, Yan-Yan Chen, Song-Lin Wan, Lu-Yao Li, Meng Xu, Jing-Jing Tong, Qun Qian, Cong-Qing Jiang, Wei-Cheng Liu
Wen-Zhe Li, Song-Lin Wan, Qun Qian, Cong-Qing Jiang, Wei-Cheng Liu, Department of Colorectal and Anal Surgery (Clinical Center for Pelvic Floor Surgery), Clinical Center of Constipation and Pelvic Floor Disease of Wuhan, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Clinical Center of Intestinal and Colorectal Diseases of Hubei Province, Quality Control Center of Colorectal and Anal Surgery of Health Commission of Hubei Province, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
Yu Xiong, Department of Radiation and Medical Oncology for Esophageal Mediastinal and Lymphatic Tumors, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
Tian-Kun Wang, Lu-Yao Li, Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
Yan-Yan Chen, Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
Meng Xu, Jing-Jing Tong, School of Life Sciences, Central China Normal University, Wuhan 430071, Hubei Province, China
Co-first authors: Wen-Zhe Li and Yu Xiong.
Author contributions: Qian Q, Jiang CQ, and Liu WC contributed to the study conception and design; Li WZ and Xiong Y performed the majority of experiments as the co-first authors of this article; Xiong Y and Wang TK performed material preparation and data collection; Chen YY contributed to the pathological diagnosis; Wan SL and Li LY performed analysis of research results; Li WZ and Xiong Y participated in the collection of patient data; Li WZ, Xiong Y, and Wang TK wrote the manuscript; Xu M and Tong JJ performed the bioinformatics analysis; Xu M performed the language revision; Liu WC secured funding for this study, supervised the experiments, and revised the manuscript. All authors read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81500505; the Construction of Predominant Disciplines of Zhongnan Hospital of Wuhan University, No. XKJS202017; the Medical Science and Technology Innovation Platform of Joint Foundation of Health Commission of Hubei Province, Zhongnan Hospital of Wuhan University, No. PTXM2021025; and the Hubei Provincial Natural Science Foundation, No. 2023AFC013.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Zhongnan Hospital of Wuhan University Institutional Review Board (Approval No. 2015048 and No. 2022156K). The use of the pathological specimens and the collection of related medical records were approved by the Ethics Committee of Zhongnan Hospital of Wuhan University (No. 2015048). All paraffin-embedded specimens preserved in the Pathology Department of Zhongnan Hospital of Wuhan University and the collection of related medical records were approved for use by the Ethics Committee of Zhongnan Hospital (No. 2022156K).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The data used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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: Wei-Cheng Liu, MD, PhD, Associate Professor, Department of Colorectal and Anal Surgery (Clinical Center for Pelvic Floor Surgery), Clinical Center of Constipation and Pelvic Floor Disease of Wuhan, Hubei Key Laboratory of Intestinal and Colorectal Diseases, Clinical Center of Intestinal and Colorectal Diseases of Hubei Province, Quality Control Center of Colorectal and Anal Surgery of Health Commission of Hubei Province, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuhan 430071, Hubei Province, China.
wb000837@whu.edu.cn
Received: March 12, 2024
Revised: September 20, 2024
Accepted: October 15, 2024
Published online: December 7, 2024
Processing time: 245 Days and 18.9 Hours
BACKGROUND
Obstructed defecation syndrome (ODS) represents the most prevalent form of chronic constipation, affecting a diverse patient population, leading to numerous complications, and imposing a significant burden on healthcare resources. Most ODS patients have insufficient rectal propulsion, but the exact mechanism underlying the pathogenesis of ODS remains unclear.
AIM
To explore the molecular mechanism underlying the pathogenesis of ODS.
METHODS
A total of 30 pairs of rectal samples were collected from patients with ODS (ODS group) or grade IV prolapsed hemorrhoids without constipation (control group) for quantitative proteomic and bioinformatic analysis. Subsequently, 50 pairs of paraffin-embedded rectal specimens were selected for immunohistochemistry and immunofluorescence studies to validate the analysis results. Human intestinal smooth cell contractile function experiments and electrophysiological experiments were conducted to verify the physiological functions of target proteins. Cellular ultrastructure was detected using transmission electron microscopy.
RESULTS
In comparison to the control group, the expression level of dystrophin (DMD) in rectal specimens from ODS patients was markedly reduced. This finding was corroborated using immunohistochemistry and immunofluorescence techniques. The diminished expression of DMD compromised the contractile function of intestinal smooth muscle cells. At the molecular level, nucleoporin protein 153 and L-type voltage-gated calcium channel were found to be overexpressed in intestinal smooth muscle cells exhibiting downregulated DMD expression. Electrophysiological experiments confirmed an excessive influx of calcium ions into these cells. Moreover, vacuolar-like structures which may be associated with excessive calcium influx were observed in the cells by transmission electron microscopy.
CONCLUSION
Decreased DMD expression in intestinal smooth muscle may upregulate L-type voltage-gated calcium channel expression, leading to excessive calcium influx which may cause a decrease in rectal propulsion, thereby contributing to the pathogenesis of ODS.
Core Tip: The long-term outcomes of numerous treatments for obstructed defecation syndrome (ODS) are now unsatisfactory. The reason is a lack of knowledge about ODS’s molecular abnormalities. Our study indicated a connection between the pathophysiology of ODS and reduced dystrophin expression. The overexpression of nucleoporin protein 153 and L-type voltage-gated calcium channel was triggered by the downregulation of dystrophin, which caused a significant flow of calcium ions into the intestinal smooth muscle cells. Overabundance of calcium ion inflow may reduce muscle contractility, which manifested as weakened rectal propulsion in ODS.
