Radiation-induced extracellular vesicles from cancer-associated fibroblasts drive oesophageal squamous cell carcinoma metastasis via the miR-193a-3p/PTEN/Akt pathway

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-09-25 DOI:10.1002/ctm2.70483

Yechun Pang, Tiantian Guo, Yue Zhou, Shanshan Jiang, Yida Li, Jianjiao Ni, Xiao Chu, Li Chu, Fangyu Chen, Xi Yang, Zhengfei Zhu

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Abstract

Background

The recurrence and metastasis of oesophageal squamous cell cancer (ESCC) following radiation therapy are major treatment challenges. Cancer-associated fibroblasts (CAFs) are key in the ESCC microenvironment, yet their role in post-radiation recurrence remains unclear.

Materials and Methods

KYSE150 ESCC cells were co-implanted with non-irradiated (0 Gy) or irradiated (8 Gy) CAFs in nude mice. CAF-derived extracellular vesicles (EVs) were isolated via differential centrifugation and analysed by electron microscopy and immunoblotting. Transwell assays evaluated EVs' effects on ESCC cell migration and invasion in vitro. RNA sequencing identified differentially expressed microRNAs, and functional experiments verified the role of miR-193a-3p. Plasma samples from 32 ESCC patients and tissue samples from 76 ESCC patients were analysed for miR-193a-3p expression.

Results

Irradiated CAFs promoted the lung metastasis of ESCC cells in vivo, and their EVs enhanced ESCC cell invasion, migration and metastasis. Elevated miR-193a-3p levels in EVs from irradiated CAFs increased miR-193a-3p expression in ESCC cells. This effect was effectively attenuated by RNase and Triton X-100 (degrading microRNAs encapsulated in EVs), or GW4869 (inhibiting EVs biogenesis and secretion)—indicating that miR-193a-3p functions in an EV-dependent manner. Knockdown of miR-193a-3p diminished the invasion, migration and epithelial–mesenchymal transition (EMT)-promoting activities of CAF-derived EVs. Luciferase assays confirmed PTEN as a target of miR-193a-3p; miR-193a-3p overexpression decreased PTEN and increased p-Akt expression. In vivo, coinjection of miR-193a-3p-knockdown CAFs with KYSE150 ESCC cells resulted in smaller tumours, fewer lung metastases, increased PTEN and E-cadherin, and decreased p-Akt and Snail expression. Clinically, radiation increased plasma exosomal miR-193a-3p levels, and high miR-193a-3p expression was correlated with shorter survival, identifying miR-193a-3p as an independent predictor of poor prognosis in ESCC patients.

Conclusion

EVs from irradiated CAFs promote ESCC metastasis via the miR-193a-3p-mediated PTEN/Akt signalling pathway. Targeting this EVs-mediated interaction represents a promising strategy for improving ESCC radiotherapy outcomes.

Key points

The poor prognosis of oesophageal squamous cell carcinoma (ESCC) is largely driven by recurrence and metastasis following radiation therapy.
Irradiated cancer-associated fibroblasts (CAFs) drive ESCC recurrence and metastasis through extracellular vesicles (EVs), highlighting their critical role in the post-radiation tumor microenvironment.
CAF-derived EVs deliver miR-193a-3p to ESCC cells, suppressing PTEN and activating Akt signaling, thereby enhancing invasion, migration, epithelialmesenchymal transition (EMT), and metastatic potential.
High plasma exosomal miR-193a-3p levels predict poor prognosis in ESCC patients and may guide therapeutic strategies after radiotherapy.

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辐射诱导的癌相关成纤维细胞外囊泡通过miR-193a-3p/PTEN/Akt通路驱动食管鳞状细胞癌转移

背景食管鳞状细胞癌（ESCC）放射治疗后的复发和转移是治疗的主要挑战。癌症相关成纤维细胞（CAFs）是ESCC微环境的关键，但其在放疗后复发中的作用尚不清楚。材料与方法将KYSE150 ESCC细胞与未辐照（0 Gy）或辐照（8 Gy）的CAFs共植入裸鼠。采用差速离心分离caf来源的细胞外囊泡，并用电镜和免疫印迹法对其进行分析。Transwell实验评估了ev对体外ESCC细胞迁移和侵袭的影响。RNA测序鉴定出差异表达的microrna，功能实验验证了miR-193a-3p的作用。对32例ESCC患者的血浆样本和76例ESCC患者的组织样本进行miR-193a-3p表达分析。结果体外照射的CAFs促进了ESCC细胞的肺转移，其ev增强了ESCC细胞的侵袭、迁移和转移。辐照的CAFs中ev中miR-193a-3p水平升高，增加了ESCC细胞中miR-193a-3p的表达。RNase和Triton X-100（降解ev中封装的microrna）或GW4869（抑制ev的生物发生和分泌）有效地减弱了这种作用，这表明miR-193a-3p以ev依赖的方式发挥作用。miR-193a-3p的敲低降低了caf衍生ev的侵袭、迁移和上皮-间质转化（EMT）促进活性。荧光素酶检测证实PTEN是miR-193a-3p的靶标；过表达miR-193a-3p可降低PTEN的表达，增加p-Akt的表达。在体内，将mir -193a-3p敲低的CAFs与KYSE150 ESCC细胞共注射，可导致肿瘤变小，肺转移减少，PTEN和E-cadherin升高，p-Akt和Snail表达降低。在临床上，放疗增加血浆外泌体miR-193a-3p水平，高miR-193a-3p表达与较短的生存期相关，这表明miR-193a-3p是ESCC患者预后不良的独立预测因子。结论来自辐照cas的ev通过mir -193a-3p介导的PTEN/Akt信号通路促进ESCC转移。靶向这种ev介导的相互作用是改善ESCC放射治疗结果的一种有希望的策略。食管鳞状细胞癌（ESCC）放疗后的复发和转移是其预后不良的主要原因。辐照后的癌症相关成纤维细胞（CAFs）通过细胞外囊泡（ev）驱动ESCC复发和转移，突出了它们在放射后肿瘤微环境中的关键作用。cafa衍生的ev将miR-193a-3p传递到ESCC细胞，抑制PTEN并激活Akt信号，从而增强侵袭、迁移、上皮间质转化（EMT）和转移潜能。血浆外泌体miR-193a-3p水平高预示ESCC患者预后不良，可能指导放疗后的治疗策略。

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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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.