染色体外DNA （ecDNA）通过染色体1q21衍生的PIP5K1A癌基因的高拷贝扩增驱动肝细胞癌恶性

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-08-25 DOI:10.1016/j.canlet.2025.218004

Ni Zhang , Xiangyu Zhang , Tinghao Yan , Fen Liu , Xinchen Tian , Changlin Ma , Huapeng Lin , Yiming Zhang , Lingli Hao , Jiaqi Zhang , Qingxia Xu , Qingbin Liu , Shulong Jiang

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引用次数: 0

摘要

染色体外环状DNA （eccDNA）在多种恶性肿瘤中驱动癌基因扩增，但其在肝细胞癌（HCC）中的表现和临床相关性仍不清楚。在这里，我们对6对HCC肿瘤和邻近的非肿瘤组织进行了Circle-seq和RNA-seq，在50%的肿瘤样本中鉴定出来自染色体1q21的3 Mb染色体外DNA （ecDNA）。该ecDNA包含多个基因，但功能分析优先考虑PIP5K1A，因为它在PI3K/AKT信号传导中起核心作用，并与不良预后相关。通过外向PCR、内向PCR、Sanger测序和荧光原位杂交（FISH）检测验证了PIP5K1A染色体外定位。Kaplan-Meier （KM）分析显示，PIP5K1A表达升高与HCC患者的不良预后相关。体内和体外实验显示，ecdna驱动的PIP5K1A扩增增强了HCC的增殖、迁移和细胞凋亡抵抗。我们的研究提供了HCC的全基因组ecDNA图谱，暗示1q21 ecDNA和PIP5K1A作为预后标记和治疗靶点，为HCC的治疗策略提供了见解。

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Extrachromosomal DNA (ecDNA) drives hepatocellular carcinoma malignancy through high-copy amplification of chromosome 1q21-derived PIP5K1A oncogene

Extrachromosomal circular DNA (eccDNA) drives oncogene amplification in multiple malignancies, yet its landscape and clinical relevance in hepatocellular carcinoma (HCC) remain poorly characterized. Here, we performed Circle-seq and RNA-seq on six pairs of HCC tumors and adjacent non-tumor tissues, identifying a 3 Mb extrachromosomal DNA (ecDNA) from chromosome 1q21 in 50 % tumor samples. This ecDNA contained multiple genes, but functional analysis prioritized PIP5K1A due to its central role in PI3K/AKT signaling and association with poor prognosis. The extrachromosomal localization of PIP5K1A was validated through outward PCR, inward PCR, Sanger sequencing, and fluorescence in situ hybridization (FISH) assays. Kaplan-Meier (KM) analysis demonstrated that elevated PIP5K1A expression was associated with an unfavorable prognosis in patients with HCC. In vivo and in vitro assays revealed that ecDNA-driven PIP5K1A amplification enhanced HCC proliferation, migration, and apoptosis resistance. Our study provides a genome-wide eccDNA profiling of HCC, implicating 1q21 ecDNA and PIP5K1A as prognostic markers and therapeutic targets, offering insights into HCC treatment strategies.

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.