Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de-palmitoylation

doi:10.1002/ctm2.1300

科研成果详情

题名	Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de-palmitoylation
作者	Shi, Zhehao 1,2; Li, Zhiming1; Jin, Bin 3,4; Ye, Wen5,6; Wang, Luhui 2; Zhang, Sina 2; Zheng, Jiuyi 2; Lin, Zixia 2; Chen, Bo 2; Liu, Fangting 2; Zhang, Baofu 2; Ding, Xiwei 7; Yang, Zhen 8; Shan, Yunfeng2,9; Yu, Zhengping2,9; Wang, Yi10; Chen, Jicai11; Chen, Qiang 12,13,15; Roberts, Lewis R. R.14; Chen, Gang2,9
发表日期	2023-06
发表期刊	CLINICAL AND TRANSLATIONAL MEDICINE 影响因子和分区
语种	英语
原始文献类型	Article
关键词	DUXAP8 ferroptosis hepatocellular carcinoma sorafenib resistance
其他关键词	LIVER-FUNCTION ; CANCER ; RESISTANCE ; DEGRADATION ; PROGRESSION ; ACTIVATION ; INVASION ; THERAPY ; HCC
摘要	BackgroundFerroptosis is an important iron-dependent form of cell death in hepatocellular carcinoma (HCC). Sorafenib, a potent ferroptosis inducer, is used to treat advanced HCC but its efficacy is limited by the development of drug resistance. MethodsThe effects of DUXAP8 expression on HCC progression were evaluated by TCGA database, Kaplan-Meier analysis, and in situ hybridization analysis. Sorafenib resistant HCC cell lines were modeled in vitro to study the regulation of DUXAP8 on ferroptosis in HCC induced by sorafenib. We used RNA pull-down, immunofluorescence assays, acyl-biotinyl exchange assay and mass spectrometry analysis to assess the molecular mechanism of ferroptosis regulation by DUXAP8. Syngeneic subcutaneous and orthotopic CDX models were used to assess whether DUXAP8 inhibition improves HCC in vivo. ResultsLncRNA DUXAP8, which is highly expressed in liver cancer and associated with poor prognosis, contributes to sorafenib resistance through suppression of ferroptosis. In vitro tests revealed that DUXAP8 reduced the sensitivity of HCC to sorafenib-induced ferroptosis by acting on SLC7A11, a subunit of the amino acid antiporter system xc-. DUXAP8 facilitates SLC7A11 palmitoylation and impedes its lysosomal degradation, thereby enhancing SLC7A11 action and suppressing ferroptosis. RNA pull-down and immunofluorescence assays confirmed that DUXAP8 decreased membrane translocation and promoted sorting of de-palmitoylated SLC7A11 to lysosomes by binding of DUXAP8 to SLC7A11. In addition, mass spectrometric analysis found that the Cys414 residue of SLC7A11 might be the predominant mutant site responsible for molecular masking of SLC7A11 lysosomal sorting. Further, the antitumor effect of DUXAP8 knockdown was verified in orthotopic and subcutaneous CDX models. ConclusionsOur findings suggest that a novel translational strategy combining sorafenib with DUXAP8 silencing to overcome drug resistance may improve treatment efficacy in patients with advanced HCC.
资助项目	National Natural Science Foundation of China [81772628, 82072685]; Medical and Health Technology Project of Zhejiang Province [2018KY124]; Science and Technology Project of Wenzhou science and technology bureau [Y2020938]
出版者	JOHN WILEY & SONS LTD
ISSN	2001-1326
卷号	13 期号:6
DOI	10.1002/ctm2.1300
页数	17
WOS类目	Oncology ; Medicine, Research & Experimental
WOS研究方向	Oncology ; Research & Experimental Medicine
WOS记录号	WOS:001008312800001
收录类别	SCIE ; PUBMED
URL	查看原文
PubMed ID	3733747
自科自定义期刊分类	T3(B)类
通讯作者地址	[Chen, Gang]Wenzhou Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Fuxue Rd, Wenzhou 325035, Zhejiang, Peoples R China. ; [Roberts, Lewis R. R.]Mayo Clin, Coll Med & Sci, Div Gastroenterol & Hepatol, 200 First St SW, Rochester, MN 55905 USA. ; [Chen, Qiang]Univ Macau, Fac Hlth Sci, Canc Ctr, Taipa, Macau Sar, Peoples R China.
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/181025
专题	公共卫生学院附属第二医院附属第一医院附属第一医院_肝胆外科附属第二医院_乳腺外科第二临床医学院、附属第二医院、育英儿童医院附属第一医院_皮肤科第一临床医学院（信息与工程学院）、附属第一医院_流行病学
通讯作者	Chen, Qiang; Roberts, Lewis R. R.; Chen, Gang
作者单位	1.Wenzhou Med Univ, Affiliated Hosp 1, Dept Dermatol, Wenzhou, Peoples R China; 2.Wenzhou Med Univ, Affiliated Hosp 1, Key Lab Diag & Treatment Severe Hepatopancreat Dis, Wenzhou, Zhejiang, Peoples R China; 3.Shandong Univ, Qilu Hosp, Cheeloo Coll Med, Dept Organ Transplantat, Jinan, Shandong, Peoples R China; 4.Shandong Univ, Hosp 2, Dept Hepatobiliary Surg, Jinan, Shandong, Peoples R China; 5.Wenzhou Med Univ, Affiliated Hosp 2, Dept Breast Surg, Wenzhou, Peoples R China; 6.Wenzhou Med Univ, Yuying Childrens Hosp, Wenzhou, Peoples R China; 7.Nanjing Univ, Med Sch, Affiliated Drum Tower Hosp, Dept Gastroenterol, Nanjing, Peoples R China; 8.Shandong Univ, Shandong Prov Hosp, Dept Infect Dis, Jinan, Peoples R China; 9.Wenzhou Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Fuxue Rd, Wenzhou 325035, Zhejiang, Peoples R China; 10.Wenzhou Med Univ, Sch Publ Hlth & Management, Dept Epidemiol & Biostat, Wenzhou, Peoples R China; 11.Wenzhou Med Univ, Affiliated Hosp 1, Dept Hernia & Abdominal Wall Surg, Wenzhou, Peoples R China; 12.Univ Macau, Fac Hlth Sci, Canc Ctr, Taipa, Macau, Peoples R China; 13.Univ Macau, MOE Frontier Sci Ctr Precis Oncol, Taipa, Macau, Peoples R China; 14.Mayo Clin, Coll Med & Sci, Div Gastroenterol & Hepatol, 200 First St SW, Rochester, MN 55905 USA; 15.Univ Macau, Fac Hlth Sci, Canc Ctr, Taipa, Macau Sar, Peoples R China
第一作者单位	附属第一医院; 皮肤科
通讯作者单位	附属第一医院; 肝胆外科
第一作者的第一单位	附属第一医院
推荐引用方式 GB/T 7714	Shi, Zhehao,Li, Zhiming,Jin, Bin,et al. Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de-palmitoylation[J]. CLINICAL AND TRANSLATIONAL MEDICINE,2023,13(6).
APA	Shi, Zhehao., Li, Zhiming., Jin, Bin., Ye, Wen., Wang, Luhui., ... & Chen, Gang. (2023). Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de-palmitoylation. CLINICAL AND TRANSLATIONAL MEDICINE, 13(6).
MLA	Shi, Zhehao,et al."Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de-palmitoylation".CLINICAL AND TRANSLATIONAL MEDICINE 13.6(2023).