中文版 | English
Title

Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma

Author
Corresponding AuthorLiu, Liping
Publication Years
2023-03-01
DOI
Source Title
ISSN
0950-9232
EISSN
1476-5594
Abstract
Emerging evidence has indicated that peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PPARGC1A) is involved in hepatocellular carcinoma (HCC). However, its detailed function and up- and downstream mechanisms are incompletely understood. In this study, we confirmed that PPAGC1A is lowly expressed in HCC and is associated with poor prognosis using large-scale public datasets and in-house cohorts. PPAGC1A was found to impair the progression and sensitivity of HCC to lenvatinib. Mechanistically, PPAGC1A repressed bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) by inhibiting WNT/beta-catenin signaling. BAMBI mediated the function of PPARGC1A and regulated ACSL5 through TGF-beta/SMAD signaling. PPARGC1A/BAMBI regulated ROS production and ferroptosis-related cell death by controlling ACSL5. PPARGC1A/BAMBI/ACSL5 axis was hypoxia-responsive. METTL3 and WTAP silenced PPARGC1A in an m6A-YTHDF2-dependent way under normoxia and hypoxia, respectively. Metformin restored PPARGC1A expression by reducing its m6A modification via inhibiting METTL3. In animal models and patient-derived organoids, consistent functional data of PPARGC1A/BAMBI/ACSL5 were observed. Conclusions: These findings provide new insights into the role of the aberrant PPARGC1A/BAMBI/ACSL5 axis in HCC. And the mechanism of PPARGC1A dysregulation was explained by m6A modification. Metformin may benefit HCC patients with PPARGC1A dysregulation.
URL[Source Record]
Indexed By
Language
English
SUSTech Authorship
Corresponding
Funding Project
China Postdoctoral Science Foundation[2021M701426] ; Shenzhen Science and Technology Innovation Commission Foundation[JCYJ20190806160412946] ; Guangdong Basic and Applied Basic Research Foundation["2021A1515220059","2019A1515110149"] ; National Natural Science Foundation of China["82002956","8140204"]
WOS Research Area
Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
WOS Subject
Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
WOS Accession No
WOS:000951990200001
Publisher
ESI Research Field
MOLECULAR BIOLOGY & GENETICS
Data Source
Web of Science
Citation statistics
Cited Times [WOS]:3
Document TypeJournal Article
Identifierhttp://kc.sustech.edu.cn/handle/2SGJ60CL/523912
DepartmentShenzhen People's Hospital
南方科技大学医学院
Affiliation
1.Jinan Univ, Shenzhen Peoples Hosp, Clin Med Coll 2, Dept Gen Surg,Div Hepatobiliary & Pancreas Surg, Shenzhen 518020, Peoples R China
2.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Peoples R China
3.Jinan Univ, Integrated Chinese & Western Med Postdoctoral Res, Guangzhou 510632, Peoples R China
4.Jinan Univ, Shenzhen Peoples Hosp, The Clin Med Coll 2, Cytotherapy Lab, Shenzhen 518020, Peoples R China
5.Huazhong Univ Sci & Technol, Union Shenzhen Hosp, Nanshan Hosp, Lab Med Ctr, Shenzhen 518000, Peoples R China
6.Southern Univ Sci & Technol, Sch Med, Shenzhen 518055, Guangdong, Peoples R China
7.Heidelberg Univ Hosp, Inst Pathol, D-69120 Heidelberg, Germany
First Author AffilicationShenzhen People's Hospital
Corresponding Author AffilicationShenzhen People's Hospital
Recommended Citation
GB/T 7714
Zhang, Qiangnu,Xiong, Lingfeng,Wei, Teng,et al. Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma[J]. ONCOGENE,2023.
APA
Zhang, Qiangnu.,Xiong, Lingfeng.,Wei, Teng.,Liu, Quan.,Yan, Lesen.,...&Liu, Liping.(2023).Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma.ONCOGENE.
MLA
Zhang, Qiangnu,et al."Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma".ONCOGENE (2023).
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