HIF‐1α‐induced long noncoding RNA LINC02776 promotes drug resistance of ovarian cancer by increasing polyADP‐ribosylation
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‐res...
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Wiley
2025-03-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70244 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yangjun Wu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5f4d5fbd30b34739a7f549aa086cb551 |
| institution | Kabale University |
| issn | 2001-1326 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj-art-5f4d5fbd30b34739a7f549aa086cb5512025-08-20T03:47:36ZengWileyClinical and Translational Medicine2001-13262025-03-01153n/an/a10.1002/ctm2.70244HIF‐1α‐induced long noncoding RNA LINC02776 promotes drug resistance of ovarian cancer by increasing polyADP‐ribosylationYangjun Wu0Yu Zeng1Yong Wu2Xinyu Ha3Zheng Feng4Chaohua Liu5Ziqi Liu6Jiajia Wang7Xingzhu Ju8Shenglin Huang9Linhui Liang10Bin Zheng11Lulu Yang12Jun Wang13Xiaohua Wu14Shengli Li15Hao Wen16Department of Gynecologic OncologyFudan University Shanghai Cancer Center, Fudan UniversityShanghai ChinaPrecision Research Center for Refractory Diseases and Shanghai Key Laboratory of Pancreatic DiseasesShanghai General Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChinaDepartment of Gynecologic OncologyFudan University Shanghai Cancer Center, Fudan UniversityShanghai ChinaDepartment of Gynecologic OncologyFudan University Shanghai Cancer Center, Fudan UniversityShanghai ChinaDepartment of Gynecologic OncologyFudan University Shanghai Cancer Center, Fudan UniversityShanghai ChinaDepartment of Gynecologic OncologyFudan University Shanghai Cancer Center, Fudan UniversityShanghai ChinaDepartment of Gynecologic OncologyFudan University Shanghai Cancer Center, Fudan UniversityShanghai ChinaDepartment of Gynecologic OncologyFudan University Shanghai Cancer Center, Fudan UniversityShanghai ChinaDepartment of Gynecologic OncologyFudan University Shanghai Cancer Center, Fudan UniversityShanghai ChinaKey Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical SciencesFudan University Shanghai Cancer Center, Fudan UniversityShanghaiChinaKey Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical SciencesFudan University Shanghai Cancer Center, Fudan UniversityShanghaiChinaAccurate International Biotechnology Co. Ltd.GuangzhouChinaWuhan Benagen Technology Co., LtdWuhanChinaWuhan Benagen Technology Co., LtdWuhanChinaDepartment of Gynecologic OncologyFudan University Shanghai Cancer Center, Fudan UniversityShanghai ChinaPrecision Research Center for Refractory Diseases and Shanghai Key Laboratory of Pancreatic DiseasesShanghai General Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChinaDepartment of Gynecologic OncologyFudan University Shanghai Cancer Center, Fudan UniversityShanghai ChinaAbstract 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.https://doi.org/10.1002/ctm2.70244HIF‐1αLINC02776ovarian cancerPARP1PARPi resistanceplatinum resistance |
| spellingShingle | 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 HIF‐1α‐induced long noncoding RNA LINC02776 promotes drug resistance of ovarian cancer by increasing polyADP‐ribosylation Clinical and Translational Medicine HIF‐1α LINC02776 ovarian cancer PARP1 PARPi resistance platinum resistance |
| title | HIF‐1α‐induced long noncoding RNA LINC02776 promotes drug resistance of ovarian cancer by increasing polyADP‐ribosylation |
| title_full | HIF‐1α‐induced long noncoding RNA LINC02776 promotes drug resistance of ovarian cancer by increasing polyADP‐ribosylation |
| title_fullStr | HIF‐1α‐induced long noncoding RNA LINC02776 promotes drug resistance of ovarian cancer by increasing polyADP‐ribosylation |
| title_full_unstemmed | HIF‐1α‐induced long noncoding RNA LINC02776 promotes drug resistance of ovarian cancer by increasing polyADP‐ribosylation |
| title_short | HIF‐1α‐induced long noncoding RNA LINC02776 promotes drug resistance of ovarian cancer by increasing polyADP‐ribosylation |
| title_sort | hif 1α induced long noncoding rna linc02776 promotes drug resistance of ovarian cancer by increasing polyadp ribosylation |
| topic | HIF‐1α LINC02776 ovarian cancer PARP1 PARPi resistance platinum resistance |
| url | https://doi.org/10.1002/ctm2.70244 |
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