In vitro-induced cancer-associated fibroblasts-derived Exosomal miRNA-224-5p targets PTEN to reduce cisplatin (DDP) sensitivity in colorectal cancer.

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Integrative biology : quantitative biosciences from nano to macro Pub Date : 2025-01-08 DOI:10.1093/intbio/zyaf022

Xiao Wu, Pengcheng Ma, Ming Zhang, Ling Wang, Aijun Wang, Yuchuan Yan, Hongyu Wang, Chao Zhang, Junwei Feng

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Abstract

Background: Cancer-associated fibroblasts (CAFs)-derived exosomes promote tumor malignancy and confer chemotherapy resistance. However, their mechanistic roles in colorectal cancer (CRC) remain incompletely understood.

Methods: Human normal colon fibroblasts were induced into CAFs using CRC cell-conditioned medium and identified by immunofluorescence. Exosomes were isolated from CAFs and characterized by Western blot, DLS analysis and cell uptake experiment. qPCR was employed to detect miRNA-224-5p expression in CAFs-derived exosomes. CCK-8 and comet assays were conducted to evaluate miRNA-224-5p's effect on cisplatin (DDP) resistance in CRC. TargetScan predicted miRNA-224-5p's downstream targets, with luciferase assays validating its interaction with PTEN. Overexpression experiments elucidated miRNA-224-5p's mechanism in DDP resistance via PTEN regulation.

Results: miRNA-224-5p was highly expressed in CAFs-derived exosomes. Functional assays revealed that exosomal miRNA-224-5p from CAFs promoted DDP resistance in CRC cells while suppressing DNA damage and apoptosis. Mechanistically, PTEN was identified as a direct target of miRNA-224-5p, through which it enhanced DDP resistance.

Conclusion: This study demonstrates that CAFs-derived exosomal miRNA-224-5p promotes DDP resistance in CRC by targeting PTEN, suggesting miRNA-224-5p as a potential therapeutic target for improving CRC treatment outcomes. Insight box MiRNA-224-5p was highly expressed in CAFs-derived exosomes. Functional assays revealed that exosomal miRNA-224-5p from CAFs promoted DDP resistance in CRC cells while suppressing DNA damage and apoptosis. PTEN was identified as a direct target of miRNA-224-5p, through which it enhanced DDP resistance.

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体外诱导的癌症相关成纤维细胞衍生的外泌体miRNA-224-5p靶向PTEN降低结直肠癌顺铂（DDP）敏感性。

背景：癌症相关成纤维细胞（CAFs）衍生的外泌体促进肿瘤恶性并赋予化疗耐药性。然而，它们在结直肠癌（CRC）中的机制作用仍不完全清楚。方法：用CRC细胞条件培养基将人正常结肠成纤维细胞诱导成CAFs，并用免疫荧光法进行鉴定。从CAFs中分离外泌体，并通过Western blot、DLS分析和细胞摄取实验对其进行表征。采用qPCR检测cafs衍生外泌体中miRNA-224-5p的表达。CCK-8和comet检测评估miRNA-224-5p对CRC顺铂（DDP）耐药的影响。TargetScan预测miRNA-224-5p的下游靶标，荧光素酶测定验证其与PTEN的相互作用。过表达实验揭示了miRNA-224-5p通过PTEN调控DDP耐药的机制。结果：miRNA-224-5p在cafs衍生的外泌体中高表达。功能分析显示，来自CAFs的外泌体miRNA-224-5p促进CRC细胞对DDP的抗性，同时抑制DNA损伤和凋亡。在机制上，PTEN被确定为miRNA-224-5p的直接靶点，通过它增强DDP抗性。结论：本研究表明，cafs来源的外泌体miRNA-224-5p通过靶向PTEN促进结直肠癌DDP耐药，提示miRNA-224-5p可能是改善结直肠癌治疗结果的潜在治疗靶点。Insight box MiRNA-224-5p在cafs衍生的外泌体中高度表达。功能分析显示，来自CAFs的外泌体miRNA-224-5p促进CRC细胞对DDP的抗性，同时抑制DNA损伤和凋亡。PTEN被确定为miRNA-224-5p的直接靶点，通过它增强DDP抗性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Integrative biology : quantitative biosciences from nano to macro

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