title: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.
abstract: Primary and acquired drug resistance is one of the main obstacles encountered in high-grade serous ovarian cancer (HGSC) chemotherapy. Cisplatin induces DNA damage through cross-linking and long integrated non-coding RNAs (lincRNAs) play an important role in chemical induced DNA-damage response, which suggests that lincRNAs may be also associated with cisplatin resistance. However, the mechanism of long integrated non-coding RNAs (lincRNAs) acting on cisplatin resistance is not well understood. Here, we showed that expression of lin-RECK-3, H19, LUCAT1, LINC00961, and linc-CARS2-2 was enhanced in cisplatin-resistant A2780-DR cells, while transcriptome sequencing showed decreased Linc-TNFRSF19-1 and LINC00515 expression. Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.
authors.affiliation: Institute of Nuclear-Agricultural Sciences, Zhejiang University, 310029, Hangzhou, China.|Institute of Zhejiang Cancer Research, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
authors.forename: Zhi-Guo
authors.initials: ZG
authors.lastname: Zheng
authors.affiliation: Institute of Nuclear-Agricultural Sciences, Zhejiang University, 310029, Hangzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Institute of Nuclear-Agricultural Sciences, Zhejiang University, 310029, Hangzhou, China.
authors.forename: Sha-Sha
authors.initials: SS
authors.lastname: Suo
authors.affiliation: Institute of Nuclear-Agricultural Sciences, Zhejiang University, 310029, Hangzhou, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Xu
authors.affiliation: Institute of Zhejiang Cancer Research, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
authors.forename: Mao-Wei
authors.initials: MW
authors.lastname: Ni
authors.affiliation: Institute of Zhejiang Cancer Research, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
authors.forename: Lin-Hui
authors.initials: LH
authors.lastname: Gu
authors.affiliation: Institute of Zhejiang Cancer Research, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Institute of Nuclear-Agricultural Sciences, Zhejiang University, 310029, Hangzhou, China.
authors.forename: Liang-Yan
authors.initials: LY
authors.lastname: Wang
authors.affiliation: Institute of Nuclear-Agricultural Sciences, Zhejiang University, 310029, Hangzhou, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Nuclear-Agricultural Sciences, Zhejiang University, 310029, Hangzhou, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Tian
authors.affiliation: Institute of Nuclear-Agricultural Sciences, Zhejiang University, 310029, Hangzhou, China.
authors.forename: Yue-Jin
authors.initials: YJ
authors.lastname: Hua
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D062085:RNA, Long Noncoding / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D005978:Glutathione; D002945:Cisplatin