Title | Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular carcinoma |
Author | |
Corresponding Author | Liu, Liping |
Publication Years | 2023-03-01
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DOI | |
Source Title | |
ISSN | 0950-9232
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EISSN | 1476-5594
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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
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SUSTech Authorship | Corresponding
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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"]
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WOS Research Area | Biochemistry & Molecular Biology
; Oncology
; Cell Biology
; Genetics & Heredity
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WOS Subject | Biochemistry & Molecular Biology
; Oncology
; Cell Biology
; Genetics & Heredity
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WOS Accession No | WOS:000951990200001
|
Publisher | |
ESI Research Field | MOLECULAR BIOLOGY & GENETICS
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Data Source | Web of Science
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Citation statistics |
Cited Times [WOS]:3
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Document Type | Journal Article |
Identifier | http://kc.sustech.edu.cn/handle/2SGJ60CL/523912 |
Department | Shenzhen 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 Affilication | Shenzhen People's Hospital |
Corresponding Author Affilication | Shenzhen 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.
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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.
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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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