DICP OpenIR
Quantitative proteomic and phosphoproteomic studies reveal novel 5-fluorouracil resistant targets in hepatocellular carcinoma
Liu, Zhen1,6; Wang, Yan1,6; Yao, Yating1,6; Fang, Zheng1,6; Miao, Qing R.2,3,4,5,7; Ye, Mingliang1,6
Corresponding AuthorMiao, Qing R.(qing.miao@nyulangone.org) ; Ye, Mingliang(mingliang@dicp.ac.cn)
KeywordHepatocellular carcinoma 5-Fu resistance LC-MS/MS GnRH signaling pathway
Source PublicationJOURNAL OF PROTEOMICS
2019-09-30
ISSN1874-3919
DOI10.1016/j.jprot.2019.103501
Volume208Pages:10
Funding ProjectChina State Key Basic Research Program[2016YFA0501402] ; China State Key Basic Research Program[2017YFA0505004] ; National Natural Science Foundation of China[21535008] ; National Natural Science Foundation of China[81600046] ; National Natural Science Foundation of China[81730016] ; National Natural Science Foundation of China[91753105] ; innovation program of science and research from the DICP, CAS[DICP TMSR201601] ; innovation program of science and research from the DICP, CAS[DICPQIBEBT UN201802] ; LiaoNing Revitalization Talents Program ; National Science Fund of China for Distinguished Young Scholars[21525524]
Funding OrganizationChina State Key Basic Research Program ; China State Key Basic Research Program ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; innovation program of science and research from the DICP, CAS ; innovation program of science and research from the DICP, CAS ; LiaoNing Revitalization Talents Program ; LiaoNing Revitalization Talents Program ; National Science Fund of China for Distinguished Young Scholars ; National Science Fund of China for Distinguished Young Scholars ; China State Key Basic Research Program ; China State Key Basic Research Program ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; innovation program of science and research from the DICP, CAS ; innovation program of science and research from the DICP, CAS ; LiaoNing Revitalization Talents Program ; LiaoNing Revitalization Talents Program ; National Science Fund of China for Distinguished Young Scholars ; National Science Fund of China for Distinguished Young Scholars ; China State Key Basic Research Program ; China State Key Basic Research Program ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; innovation program of science and research from the DICP, CAS ; innovation program of science and research from the DICP, CAS ; LiaoNing Revitalization Talents Program ; LiaoNing Revitalization Talents Program ; National Science Fund of China for Distinguished Young Scholars ; National Science Fund of China for Distinguished Young Scholars ; China State Key Basic Research Program ; China State Key Basic Research Program ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; innovation program of science and research from the DICP, CAS ; innovation program of science and research from the DICP, CAS ; LiaoNing Revitalization Talents Program ; LiaoNing Revitalization Talents Program ; National Science Fund of China for Distinguished Young Scholars ; National Science Fund of China for Distinguished Young Scholars
WOS SubjectBiochemical Research Methods
WOS Research AreaBiochemistry & Molecular Biology
WOS KeywordFOCAL ADHESION KINASE ; PHOSPHORYLATION ; EXPRESSION ; NETWORKS ; PROTEINS ; THERAPY ; CELLS
AbstractThe development of chemoresistance remains the major obstacles to successful chemotherapy of hepatocellular carcinoma. The molecular mechanisms of drug resistance are complex. Identifying the key markers is crucial for development of therapeutic strategies to overcome resistance. In this study, we employed a cell-line model consisting of the 5-fluorouracil resistant Bel/5-Fu cell line and its parental Bel cell line. Using stable isotope dimethyl labeling combined with high-resolution mass spectrometry, in total, 8272 unique proteins and 22,095 phosphorylation sites with high localization confidence were identified. Our data indicated that the GnRH signaling pathway was involved in acquiring drug resistance, which has not been well elucidated. The western blotting results confirmed that the expression levels of PLC beta 3 and PLC beta 3 pS1105 in Bel/5-Fu cells were increased as compared to Bel cells. Furthermore, the protein levels of SRC and PKG delta, which could phosphorylate PLC beta 3 at ser1105, were higher in Bel/5-Fu cells than in Bel cells. The knockdown of SRC, PKC delta and PLC beta 3 increased the susceptibility of Bel/5-Fu cells to 5-Fu. Besides, the increased transcription levels of PLC beta 3, PRC delta and SRC were significantly associated with decreased overall survival. Together, our deep proteomic and phosphoproteomic data reveal novel therapeutic targets for attenuating 5-Fu resistance in anti-cancer therapy. Significance: It was reported that many hepatocellular carcinoma patients are resistance to 5-Fu. Although some studies related to drug resistance have been reported, the underlying mechanisms were not well elucidated. Unlike many single molecular studies, we focused on the global proteome and phosphoproteome analysis of Bel and Be15-/Fu cell line using stable isotope dimethyl labeling to identify the previously unrecognized signaling pathway for causing 5-Fu resistance. Our results showed that the phosphorylation levels of PLC beta 3 pS1105 and the protein levels of PLC beta 3, PKC delta and SRC, which are major components of GnRH signaling pathway were higher in Bel/5-Fu cells than in Bel cells. Furthermore, knockdown of PLC beta 3, PKC delta and SRC increased the susceptibility of Bel/5-Fu cells to 5-Fu. Overall, this is the first comprehensive proteomic and phosphoproteomic studies on 5-Fu resistant cell line Bel/5-Fu to identify the potential targets of attenuating chemoresistance in hepatocellular carcinoma.
Language英语
Funding OrganizationChina State Key Basic Research Program ; China State Key Basic Research Program ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; innovation program of science and research from the DICP, CAS ; innovation program of science and research from the DICP, CAS ; LiaoNing Revitalization Talents Program ; LiaoNing Revitalization Talents Program ; National Science Fund of China for Distinguished Young Scholars ; National Science Fund of China for Distinguished Young Scholars ; China State Key Basic Research Program ; China State Key Basic Research Program ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; innovation program of science and research from the DICP, CAS ; innovation program of science and research from the DICP, CAS ; LiaoNing Revitalization Talents Program ; LiaoNing Revitalization Talents Program ; National Science Fund of China for Distinguished Young Scholars ; National Science Fund of China for Distinguished Young Scholars ; China State Key Basic Research Program ; China State Key Basic Research Program ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; innovation program of science and research from the DICP, CAS ; innovation program of science and research from the DICP, CAS ; LiaoNing Revitalization Talents Program ; LiaoNing Revitalization Talents Program ; National Science Fund of China for Distinguished Young Scholars ; National Science Fund of China for Distinguished Young Scholars ; China State Key Basic Research Program ; China State Key Basic Research Program ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; innovation program of science and research from the DICP, CAS ; innovation program of science and research from the DICP, CAS ; LiaoNing Revitalization Talents Program ; LiaoNing Revitalization Talents Program ; National Science Fund of China for Distinguished Young Scholars ; National Science Fund of China for Distinguished Young Scholars
WOS IDWOS:000487172100017
PublisherELSEVIER
Citation statistics
Cited Times:1[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/172657
Collection中国科学院大连化学物理研究所
Corresponding AuthorMiao, Qing R.; Ye, Mingliang
Affiliation1.Chinese Acad Sci, Natl Chromatog R&A Ctr, Dalian Inst Chem Phys, CAS Key Lab Separat Sci Analyt Chem, Dalian 116023, Peoples R China
2.Med Coll Wisconsin, Childrens Res Inst, Dept Surg, Div Pediat Surg, Milwaukee, WI 53226 USA
3.Med Coll Wisconsin, Childrens Res Inst, Dept Surg, Div Pediat Pathol, Milwaukee, WI 53226 USA
4.Med Coll Wisconsin, Childrens Res Inst, Dept Pathol, Div Pediat Surg, Milwaukee, WI 53226 USA
5.Med Coll Wisconsin, Childrens Res Inst, Dept Pathol, Div Pediat Pathol, Milwaukee, WI 53226 USA
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.NYU, Winthrop Hosp, Mineola, NY 11501 USA
Recommended Citation
GB/T 7714
Liu, Zhen,Wang, Yan,Yao, Yating,et al. Quantitative proteomic and phosphoproteomic studies reveal novel 5-fluorouracil resistant targets in hepatocellular carcinoma[J]. JOURNAL OF PROTEOMICS,2019,208:10.
APA Liu, Zhen,Wang, Yan,Yao, Yating,Fang, Zheng,Miao, Qing R.,&Ye, Mingliang.(2019).Quantitative proteomic and phosphoproteomic studies reveal novel 5-fluorouracil resistant targets in hepatocellular carcinoma.JOURNAL OF PROTEOMICS,208,10.
MLA Liu, Zhen,et al."Quantitative proteomic and phosphoproteomic studies reveal novel 5-fluorouracil resistant targets in hepatocellular carcinoma".JOURNAL OF PROTEOMICS 208(2019):10.
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