SOX4 mediates cancer-associated fibroblasts related radioresistance in hepatocellular carcinoma.

IF 4.8 2区医学 Q1 Medicine

Cellular Oncology Pub Date : 2025-07-30 DOI:10.1007/s13402-025-01088-z

Ke Jiang, Botian Huang, Shasha He, Meiyan Zhu, Xiao Zhao, Miaowen Liu, Zhenwei Peng, Yan Wang, Yong Chen

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引用次数: 0

Abstract

Purpose: Cancer-associated fibroblasts (CAFs), a crucial component of tumor microenvironment, play a critical role in tumorigenesis, progression, and conferring resistance to radiotherapy and chemotherapy. This study aimed to investigate the association between CAFs, CAF- related genes, and radioresistance in hepatocellular carcinoma (HCC).

Methods: CAFs were isolated from HCC tissues and subsequently utilized for co-culturing with HCC cells using CAFs-conditioned medium. An orthotopic HCC mouse model was established by co-implanting CAFs and HCC cells. Through integrative analysis of three RNA-sequencing datasets (TCGA-LIHC tumor vs. normal tissues, Huh7 radioresistant vs. parent cells, and CAF vs. control group), CAF-associated prognostic genes were identified using comprehensive bioinformatics approaches. Experimental validation was performed by real-time quantitative PCR, western blot, immunohistochemistry, cell viability assays, and colony formation assays.

Results: Our findings demonstrated that CAFs significantly enhance radioresistance in HCC. Based on 13 CAF-related prognostic genes, TCGA-LIHC patients were stratified into two distinct clusters via consensus clustering, exhibiting significant differences in overall survival, immune cell infiltration, and therapeutic response. A prognostic nomogram incorporating three hub genes and clinical characteristics was developed. Notably, SOX4 was upregulated in tumor tissues, radioresistant cells, and CAF-exposed HCC cells, correlating with poor prognosis. SOX4 knockdown suppressed HCC proliferation and reversed CAF-induced radioresistance. Additionally, a competitive endogenous RNA (ceRNA) network of LINC00665/miR-122-5p/SOX4 was constructed.

Conclusion: CAFs serve as crucial mediators of radioresistance in HCC, and CAF-related genes provide valuable prognostic and therapeutic insights. SOX4 emerges as a promising therapeutic target to improve radiotherapy efficacy in HCC.

Clinical trial number: Not applicable.

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SOX4介导肝癌中癌相关成纤维细胞相关放射耐药

目的：肿瘤相关成纤维细胞（Cancer-associated fibroblasts, CAFs）是肿瘤微环境的重要组成部分，在肿瘤的发生、发展和对放疗和化疗的耐药性中起着关键作用。本研究旨在探讨CAF、CAF相关基因与肝细胞癌（HCC）放射耐药之间的关系。方法：从HCC组织中分离出CAFs，随后使用CAFs条件培养基与HCC细胞共培养。采用人工肝细胞与肝癌细胞共植的方法建立原位肝癌小鼠模型。通过对三个rna测序数据集（TCGA-LIHC肿瘤与正常组织，Huh7放射耐药与亲本细胞，CAF与对照组）的综合分析，利用综合生物信息学方法确定了CAF相关的预后基因。通过实时定量PCR、western blot、免疫组织化学、细胞活力测定和菌落形成测定进行实验验证。结果：我们的研究结果表明，CAFs可显著增强HCC的放射耐药。基于13个ca相关的预后基因，通过共识聚类将TCGA-LIHC患者分为两个不同的簇，在总生存、免疫细胞浸润和治疗反应方面存在显著差异。结合三个中心基因和临床特征的预后图被开发。值得注意的是，SOX4在肿瘤组织、放射耐药细胞和ca暴露的HCC细胞中表达上调，与预后不良相关。SOX4敲除抑制HCC增殖并逆转钙诱导的放射耐药。此外，我们构建了LINC00665/miR-122-5p/SOX4竞争性内源性RNA （ceRNA）网络。结论：肝细胞癌是肝细胞癌放射耐药的重要介质，肝细胞癌相关基因为预后和治疗提供了有价值的见解。SOX4有望成为提高肝癌放疗疗效的治疗靶点。临床试验号：不适用。

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

Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research

CiteScore

10.40

自引率

1.50%

发文量

审稿时长

16 weeks

期刊介绍： The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.