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.

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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.