PMID- 35085814
OWN - NLM
STAT- MEDLINE
DCOM- 20220411
LR  - 20230407
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 30
IP  - 4
DP  - 2022 Apr 6
TI  - Mitochondrial fragmentation is crucial for c-Myc-driven hepatoblastoma-like liver 
      tumors.
PG  - 1645-1660
LID - S1525-0016(22)00032-6 [pii]
LID - 10.1016/j.ymthe.2022.01.032 [doi]
AB  - Hepatoblastoma is the most common liver cancer in children, and the aggressive 
      subtype often has a poor prognosis and lacks effective targeted therapy. Although 
      aggressive hepatoblastoma (HB) is often accompanied by abnormally high expression 
      of the transcription factor c-Myc, the underlying mechanism remains unclear. In 
      this study, we found that mitochondrial fragmentation was enhanced by c-Myc 
      overexpression in human aggressive HB tissues and was associated with poor 
      prognosis. Then, a mouse model resembling human HB was established via 
      hydrodynamic injection of c-Myc plasmids. We observed that liver-specific 
      knockout of the mitochondrial fusion molecule MFN1 or overexpression of 
      mitochondrial fission molecule DRP1 promoted the occurrence of c-Myc-driven liver 
      cancer. In contrast, when MFN1 was overexpressed in the liver, tumor formation 
      was delayed. In vitro experiments showed that c-Myc transcriptionally upregulated 
      the expression of DRP1 and decreased MFN1 expression through upregulation of 
      miR-373-3p. Moreover, enhanced mitochondrial fragmentation significantly promoted 
      aerobic glycolysis and the proliferation of HB cells by significantly increasing 
      reactive oxygen species (ROS) production and activating the RAC-alpha 
      serine/threonine-protein kinase (AKT)/mammalian target of rapamycin (mTOR) and 
      nuclear factor kappaB (NF-kappaB) pathways. Taken together, our results indicate that 
      c-Myc-mediated mitochondrial fragmentation promotes the malignant transformation 
      and progression of HB by activating ROS-mediated multi-oncogenic signaling.
CI  - Copyright (c) 2022. Published by Elsevier Inc.
FAU - Wang, Dalin
AU  - Wang D
AD  - State Key Laboratory of Cancer Biology and Department of Physiology and 
      Pathophysiology, Fourth Military Medical University, Xi'an 710032, China; 
      Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical 
      University, Xi'an 710032, China.
FAU - Tian, Jiming
AU  - Tian J
AD  - The First Clinical Medical College of Lanzhou University, Lanzhou 730099, China.
FAU - Yan, Zeyu
AU  - Yan Z
AD  - Department of General Surgery, Tangdu Hospital, Fourth Military Medical 
      University, Xi'an 710038, China.
FAU - Yuan, Qing
AU  - Yuan Q
AD  - Institute of Medical Research, Northwestern Polytechnical University, Xi'an 
      710072, China.
FAU - Wu, Dan
AU  - Wu D
AD  - State Key Laboratory of Cancer Biology and Department of Physiology and 
      Pathophysiology, Fourth Military Medical University, Xi'an 710032, China.
FAU - Liu, Xiaoli
AU  - Liu X
AD  - State Key Laboratory of Cancer Biology and Department of Physiology and 
      Pathophysiology, Fourth Military Medical University, Xi'an 710032, China.
FAU - Yang, Shirong
AU  - Yang S
AD  - Department of General Surgery, Tangdu Hospital, Fourth Military Medical 
      University, Xi'an 710038, China.
FAU - Guo, Shanshan
AU  - Guo S
AD  - State Key Laboratory of Cancer Biology and Department of Physiology and 
      Pathophysiology, Fourth Military Medical University, Xi'an 710032, China.
FAU - Wang, Jianxun
AU  - Wang J
AD  - Department of General Surgery, 986th Hospital of Air Force, Xi'an 710054, China.
FAU - Yang, Yongxiu
AU  - Yang Y
AD  - The First Clinical Medical College of Lanzhou University, Lanzhou 730099, China.
FAU - Xing, Jinliang
AU  - Xing J
AD  - State Key Laboratory of Cancer Biology and Department of Physiology and 
      Pathophysiology, Fourth Military Medical University, Xi'an 710032, China.
FAU - An, Jiaze
AU  - An J
AD  - Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical 
      University, Xi'an 710032, China. Electronic address: anchen@fmmu.edu.cn.
FAU - Huang, Qichao
AU  - Huang Q
AD  - State Key Laboratory of Cancer Biology and Department of Physiology and 
      Pathophysiology, Fourth Military Medical University, Xi'an 710032, China. 
      Electronic address: huangqichao@fmmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220124
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (MicroRNAs)
RN  - 0 (Reactive Oxygen Species)
SB  - IM
MH  - Animals
MH  - *Hepatoblastoma/genetics/metabolism/pathology
MH  - *Liver Neoplasms/metabolism
MH  - Mammals
MH  - Mice
MH  - *MicroRNAs
MH  - Reactive Oxygen Species
MH  - Signal Transduction
PMC - PMC9077476
OTO - NOTNLM
OT  - Drp1
OT  - Mfn1
OT  - ROS
OT  - c-Myc
OT  - hepatoblastoma
OT  - mitochondrial fragmentation
COIS- Declaration of interest The authors declare no competing interests.
EDAT- 2022/01/28 06:00
MHDA- 2022/04/12 06:00
PMCR- 2023/04/06
CRDT- 2022/01/27 20:13
PHST- 2021/06/23 00:00 [received]
PHST- 2021/11/19 00:00 [revised]
PHST- 2022/01/20 00:00 [accepted]
PHST- 2022/01/28 06:00 [pubmed]
PHST- 2022/04/12 06:00 [medline]
PHST- 2022/01/27 20:13 [entrez]
PHST- 2023/04/06 00:00 [pmc-release]
AID - S1525-0016(22)00032-6 [pii]
AID - 10.1016/j.ymthe.2022.01.032 [doi]
PST - ppublish
SO  - Mol Ther. 2022 Apr 6;30(4):1645-1660. doi: 10.1016/j.ymthe.2022.01.032. Epub 2022 
      Jan 24.