PMID- 35721496
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220716
IS  - 2296-634X (Print)
IS  - 2296-634X (Electronic)
IS  - 2296-634X (Linking)
VI  - 10
DP  - 2022
TI  - HIF-1/2alpha-Activated RNF146 Enhances the Proliferation and Glycolysis of 
      Hepatocellular Carcinoma Cells via the PTEN/AKT/mTOR Pathway.
PG  - 893888
LID - 10.3389/fcell.2022.893888 [doi]
LID - 893888
AB  - Hypoxia microenvironment, a critical feature of hepatocellular carcinoma, 
      contributes to hepatocarcinogenesis, tumor progression and therapeutic 
      resistance. Hypoxia-inducible factors (HIFs)-activated target genes are the main 
      effectors in hypoxia-induced HCC progression. In this study, we identified 
      ubiquitin E3 ligase ring finger protein 146 (RNF146) as a novel HIFs target gene. 
      Either HIF-1alpha or HIF-2alpha knockdown significantly repressed hypoxia-induced RNF146 
      upregulation in Hep3B and Huh7 cells. TCGA data and our immunohistochemistry 
      analysis consistently revealed the overexpression of RNF146 in HCC tissues. The 
      upregulated expression of RNF146 was also detected in HCC cell lines. The high 
      RNF146 level was correlated with poor clinical features and predicted a shorter 
      overall survival of patients with HCC. RNF146 knockdown suppressed the 
      proliferation, colony formation and glycolysis of HCC cells, but suppressed but 
      RNF146 overexpression promoted these malignant behaviors. Moreover, RNF146 
      silencing weakened HCC growth in mice. RNF146 inversely regulated phosphatase and 
      tensin homolog (PTEN) protein level, thereby activating the AKT/mechanistic 
      target of rapamycin kinase (mTOR) pathway in HCC cells. MG132 reversed RNF146 
      overexpression-induced PTEN reduction. RNF146 knockdown decreased the 
      ubiquitination and degradation of PTEN in HCC cells. Therefore, we clarified that 
      PTEN knockdown notably abolished the effects of RNF146 silencing on the AKT/mTOR 
      pathway and Hep3B cells' proliferation, colony formation and glycolysis. To 
      conclude, our data confirmed that RNF146 was transcriptionally regulated by 
      HIF-1/2alpha and activated the AKT/mTOR pathway by promoting the ubiquitin 
      proteolysis of PTEN, thereby contributing to HCC progression. RNF146 may be a 
      potential new drug target for anti-HCC.
CI  - Copyright (c) 2022 Shen, Wang, Zhu, Lu, Liu, Xu and Huang.
FAU - Shen, Guoliang
AU  - Shen G
AD  - Department of Clinical Medicine, Medical College of Soochow University, Suzhou, 
      China.
AD  - Department of General Surgery, Zhejiang Provincial People's Hospital, Affiliated 
      People's Hospital, Hangzhou Medical College, Hangzhou, China.
FAU - Wang, Hao
AU  - Wang H
AD  - Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an 
      Jiaotong University, Xi'an, China.
FAU - Zhu, Ning
AU  - Zhu N
AD  - The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of 
      Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's 
      Hospital, Hangzhou Medical College, Hangzhou, China.
FAU - Lu, Qiliang
AU  - Lu Q
AD  - The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of 
      Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's 
      Hospital, Hangzhou Medical College, Hangzhou, China.
FAU - Liu, Junwei
AU  - Liu J
AD  - Department of General Surgery, Zhejiang Provincial People's Hospital, Affiliated 
      People's Hospital, Hangzhou Medical College, Hangzhou, China.
FAU - Xu, Qiuran
AU  - Xu Q
AD  - The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of 
      Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's 
      Hospital, Hangzhou Medical College, Hangzhou, China.
FAU - Huang, Dongsheng
AU  - Huang D
AD  - The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of 
      Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's 
      Hospital, Hangzhou Medical College, Hangzhou, China.
LA  - eng
PT  - Journal Article
DEP - 20220527
PL  - Switzerland
TA  - Front Cell Dev Biol
JT  - Frontiers in cell and developmental biology
JID - 101630250
PMC - PMC9200061
OTO - NOTNLM
OT  - RNF146
OT  - akt/mtor pathway
OT  - hepatocellular carcinoma
OT  - hypoxia microenvironment
OT  - pten
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/06/21 06:00
MHDA- 2022/06/21 06:01
PMCR- 2022/01/01
CRDT- 2022/06/20 03:55
PHST- 2022/03/11 00:00 [received]
PHST- 2022/05/09 00:00 [accepted]
PHST- 2022/05/09 00:00 [accepted]
PHST- 2022/06/20 03:55 [entrez]
PHST- 2022/06/21 06:00 [pubmed]
PHST- 2022/06/21 06:01 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 893888 [pii]
AID - 10.3389/fcell.2022.893888 [doi]
PST - epublish
SO  - Front Cell Dev Biol. 2022 May 27;10:893888. doi: 10.3389/fcell.2022.893888. 
      eCollection 2022.