HIF-1α-induced long noncoding RNA LINC02776 promotes drug resistance of ovarian cancer by increasing polyADP-ribosylation

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-03-21 DOI:10.1002/ctm2.70244

Yangjun Wu, Yu Zeng, Yong Wu, Xinyu Ha, Zheng Feng, Chaohua Liu, Ziqi Liu, Jiajia Wang, Xingzhu Ju, Shenglin Huang, Linhui Liang, Bin Zheng, Lulu Yang, Jun Wang, Xiaohua Wu, Shengli Li, Hao Wen

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引用次数: 0

Abstract

Background

Chemoresistance remains a major hurdle in ovarian cancer (OC) treatment, as many patients eventually develop resistance to platinum-based chemotherapy and/or PARP inhibitors (PARPi).

Methods

We performed transcriptome-wide analysis by RNA sequencing (RNA-seq) data of platinum-resistant and -sensitive OC tissues. We demonstrated the role of LINC02776 in platinum resistance in OC cells, mice models and patient-derived organoid (PDO) models.

Results

We identify the long noncoding RNA LINC02776 as a critical factor of platinum resistance. Elevated expression of LINC02776 is observed in platinum-resistant OC and serves as an independent prognostic factor for OC patients. Functionally, silencing LINC02776 reduces proliferation and DNA damage repair in OC cells, thereby enhancing sensitivity to platinum and PARPi in both xenograft mouse models and patient-derived organoid (PDO) models with acquired chemoresistance. Mechanistically, LINC02776 binds to the catalytic domain of poly (ADP-ribose) polymerase 1 (PARP1), promoting PARP1-dependent polyADP-ribosylation (PARylation) and facilitating homologous recombination (HR) restoration. Additionally, high HIF-1α expression in platinum-resistant tissues further stimulates LINC02776 transcription.

Conclusions

Our findings suggest that targeting LINC02776 represents a promising therapeutic strategy for OC patients who have developed resistance to platinum or PARPi.

Key points

LINC02776 promotes OC cell proliferation by regulating DNA damage and apoptosis signaling pathways.
LINC02776 binds PARP1 to promote DNA damage-triggered PARylation in OC cells.
LINC02776 mediates cisplatin and olaparib resistance in OC cells by enhancing PARP1-mediated PARylation activity and regulating the PARP1-mediated HR pathway.
The high expression of LINC02776 is induced by HIF-1α in platinum-resistant OC cells and tissues.

Abstract Image

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hif -1α-诱导的长链非编码RNA LINC02776通过增加聚adp核糖基化促进卵巢癌耐药。

背景：化疗耐药仍然是卵巢癌（OC）治疗的主要障碍，因为许多患者最终对铂类化疗和/或PARP抑制剂（PARPi）产生耐药性。方法：我们通过RNA测序（RNA-seq）数据对铂耐药和铂敏感的OC组织进行转录组分析。我们在OC细胞、小鼠模型和患者源性类器官（PDO）模型中证明了LINC02776在铂耐药中的作用。结果：我们发现长链非编码RNA LINC02776是铂耐药的关键因素。在铂耐药OC中观察到LINC02776的表达升高，并作为OC患者的独立预后因素。在功能上，沉默LINC02776可减少OC细胞的增殖和DNA损伤修复，从而增强异种移植小鼠模型和获得性化疗耐药的患者源性类器官（PDO）模型对铂和PARPi的敏感性。从机制上讲，LINC02776与聚（adp -核糖）聚合酶1 （PARP1）的催化结构域结合，促进PARP1依赖的聚adp -核糖基化（PARylation）和促进同源重组（HR）恢复。此外，HIF-1α在铂耐药组织中的高表达进一步刺激LINC02776的转录。结论：我们的研究结果表明，靶向LINC02776对于铂或PARPi耐药的OC患者是一种很有前景的治疗策略。重点：LINC02776通过调节DNA损伤和凋亡信号通路促进OC细胞增殖。LINC02776结合PARP1促进OC细胞中DNA损伤触发的PARylation。LINC02776通过增强parp1介导的PARylation活性和调节parp1介导的HR通路，介导OC细胞对顺铂和奥拉帕尼的耐药。HIF-1α诱导LINC02776在耐铂OC细胞和组织中高表达。

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.