دورية أكاديمية
أعرض في EDS

Combining proteomics and Phosphoproteomics to investigate radiation-induced rectal fibrosis in rats and the effects of pSTAT3 inhibitor S3I-201 on human intestinal fibroblasts.

التفاصيل البيبلوغرافية
العنوان: Combining proteomics and Phosphoproteomics to investigate radiation-induced rectal fibrosis in rats and the effects of pSTAT3 inhibitor S3I-201 on human intestinal fibroblasts.
المؤلفون: Pan H; Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China., Zhao Z; Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China., Zhu Y; Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China., Gao Y; Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China., Ruan H; Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China., Huang Y; Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China. Electronic address: fuzhouwushan@foxmail.com., Chi P; Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China. Electronic address: chipan363@163.com., Huang S; Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China. Electronic address: shepherd819@fjmu.edu.cn.
المصدر: Journal of proteomics [J Proteomics] 2024 Sep 30; Vol. 308, pp. 105287. Date of Electronic Publication: 2024 Aug 21.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101475056 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1876-7737 (Electronic) Linking ISSN: 18743919 NLM ISO Abbreviation: J Proteomics Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Amsterdam : Elsevier
مواضيع طبية MeSH: STAT3 Transcription Factor*/metabolism , Proteomics*/methods , Fibroblasts*/metabolism , Fibroblasts*/drug effects , Fibroblasts*/radiation effects , Rats, Sprague-Dawley* , Fibrosis* , Aminosalicylic Acids*/pharmacology, Animals ; Humans ; Rats ; Rectum/radiation effects ; Rectum/drug effects ; Rectum/pathology ; Phosphoproteins/metabolism ; Male ; Benzenesulfonates
مستخلص: Objective: To investigate the regulatory mechanisms of radiation-induced rectal fibrosis (RIRF) and assess the therapeutic potential of S3I-201.
Methods: Sprague-Dawley rats were divided into control and radiation groups, with the latter exposed to 20 Gray pelvic X-rays. After 10 weeks, rectal tissues were analyzed using tandem mass tag (TMT) proteomics and phosphoproteomics. Pathway enrichment was performed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, with secondary annotation using Cluego. Representative proteins and their phosphorylated counterparts were validated through immunoblotting in another cohort. STAT3 levels in rectal tissues from irradiated and non-irradiated colorectal cancer patients were examined, and the effects of S3I-201 on human rectal fibroblasts were evaluated.
Results: The radiation group showed significant inflammatory responses and collagen deposition in the rat rectal walls. Enrichment analysis revealed that radiation-induced proteins and phosphoproteins were primarily involved in extracellular matrix-receptor interaction and the MAPK signaling pathway. Immunoblotting indicated increased expression of p-CAMKII, p-MRACKS, p-Cfl1, p-Myl9, and p-STAT3 in the radiation group compared to the control, while p-AKT1 expression decreased. Elevated phosphorylation of STAT3 was observed in submucosal fibroblasts of the post-radiation human rectum. S3I-201 specifically inhibited STAT3 phosphorylation and suppressed activation of human rectal fibroblasts, also inhibiting the pro-fibrotic effects of the classical TGF-β/Smad/CTGF pathway.
Conclusion: By integrating phosphoproteomics and proteomics, this study elucidated the protein regulatory network of RIRF and identified the potential therapeutic targets, including phosphoproteins such as STAT3 in managing RIRF.
Significance: In our research, we employed TMT labeling alongside LC-MS/MS techniques to comprehensively explore the proteomic and phosphoproteomic landscapes in rat models of radiation-induced intestinal fibrosis (RIRF). Our analysis revealed the function and pathways of proteins and phosphorylated proteins triggered by radiation, as well as those with protective roles. We mapped a network of interactions among these proteins and validated key protein expression levels using quantitative methods. Furthermore, we investigated STAT3 as a potential therapeutic target, assessing the efficacy of the inhibitor S3I-201 in laboratory settings, and highlighting its potential for RIRF treatment. Overall, our findings provide groundbreaking insights into the mechanisms underlying RIRF, paving the way for the development of future antifibrotic therapies.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
فهرسة مساهمة: Keywords: Phosphoproteomics; Proteomics; Radiation-induced fibrosis; S3I-201; STAT3
المشرفين على المادة: 0 (STAT3 Transcription Factor)
0 (Aminosalicylic Acids)
0 (NSC 74859)
0 (Phosphoproteins)
0 (STAT3 protein, human)
0 (Stat3 protein, rat)
0 (Benzenesulfonates)
تواريخ الأحداث: Date Created: 20240822 Date Completed: 20240909 Latest Revision: 20240909
رمز التحديث: 20240910
DOI: 10.1016/j.jprot.2024.105287
PMID: 39173903
قاعدة البيانات: MEDLINE
الوصف
تدمد:1876-7737
DOI:10.1016/j.jprot.2024.105287