PMID- 37104068
OWN - NLM
STAT- MEDLINE
DCOM- 20230508
LR  - 20230527
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 37
IP  - 6
DP  - 2023 Jun
TI  - Thioredoxin facilitates hepatocellular carcinoma stemness and metastasis by 
      increasing BACH1 stability to activate the AKT/mTOR pathway.
PG  - e22943
LID - 10.1096/fj.202300050RR [doi]
AB  - Thioredoxin (TXN) is essential for preserving balance and controlling the 
      intracellular redox state. Most studies have focused on the function of TXN in 
      redox reactions, which is critical for tumor progression. Here, we showed that 
      TXN promotes hepatocellular carcinoma (HCC) stemness properties in a 
      non-redox-dependent manner, which has rarely been reported in previous studies. 
      TXN exhibited upregulated expression in human HCC specimens, which was associated 
      with a poor prognosis. Functional studies showed that TXN promoted HCC stemness 
      properties and facilitated HCC metastasis both in vitro and in vivo. 
      Mechanistically, TXN promoted the stemness of HCC cells by interacting with BTB 
      and CNC homology 1 (BACH1) and stabilized BACH1 expression by inhibiting its 
      ubiquitination. BACH1 was positively correlated with TXN expression and was 
      significantly upregulated in HCC. In addition, BACH1 promotes HCC stemness by 
      activating the AKT/mammalian target of rapamycin (mTOR) pathway. Furthermore, we 
      found that the specific inhibition of TXN in combination with lenvatinib in mice 
      significantly improved the treatment of metastatic HCC. In summary, our data 
      demonstrate that TXN plays a crucial role in HCC stemness and BACH1 plays an 
      integral part in regulating this process by activating the AKT/mTOR pathway. 
      Thus, TXN is a promising target for metastatic HCC therapy.
CI  - (c) 2023 Federation of American Societies for Experimental Biology.
FAU - Wang, Chengmeng
AU  - Wang C
AUID- ORCID: 0000-0002-2822-3009
AD  - Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical 
      University Cancer Institute and Hospital, Tianjin, China.
AD  - National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention 
      and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
FAU - Zhang, Lu
AU  - Zhang L
AD  - Department of Pulmonology, Tianjin Children's Hospital/Tianjin University 
      Children's Hospital, Tianjin, China.
FAU - Cao, Manqing
AU  - Cao M
AD  - National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention 
      and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
AD  - Department of Breast Surgery, Tianjin Medical University Cancer Institute and 
      Hospital, Tianjin, China.
FAU - Fu, Zhou
AU  - Fu Z
AD  - Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical 
      University Cancer Institute and Hospital, Tianjin, China.
AD  - National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention 
      and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
FAU - Wang, Huaqi
AU  - Wang H
AD  - Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical 
      University Cancer Institute and Hospital, Tianjin, China.
AD  - National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention 
      and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
FAU - Zhang, Su
AU  - Zhang S
AD  - National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention 
      and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
AD  - Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute 
      and Hospital, Tianjin, China.
FAU - Zhu, Keyun
AU  - Zhu K
AD  - Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical 
      University Cancer Institute and Hospital, Tianjin, China.
AD  - National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention 
      and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
FAU - Hou, Zhenyu
AU  - Hou Z
AD  - Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical 
      University Cancer Institute and Hospital, Tianjin, China.
AD  - National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention 
      and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
FAU - Cui, Jinfang
AU  - Cui J
AD  - National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention 
      and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
AD  - Department of Thoracic Oncology, Lung Cancer Diagnosis and Treatment Center, 
      Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
FAU - Yue, Ping
AU  - Yue P
AD  - National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention 
      and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
AD  - Department of Thoracic Oncology, Lung Cancer Diagnosis and Treatment Center, 
      Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
FAU - Guo, Hua
AU  - Guo H
AD  - National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention 
      and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
AD  - Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and 
      Hospital, Tianjin, China.
FAU - Zhang, Ti
AU  - Zhang T
AUID- ORCID: 0000-0002-8759-4395
AD  - Department of Hepatobiliary Cancer, Liver Cancer Research Center, Tianjin Medical 
      University Cancer Institute and Hospital, Tianjin, China.
AD  - National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention 
      and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
AD  - Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 
      China.
AD  - Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 
      China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (BACH1 protein, human)
RN  - 0 (Bach1 protein, mouse)
RN  - 0 (Basic-Leucine Zipper Transcription Factors)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - 52500-60-4 (Thioredoxins)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Basic-Leucine Zipper Transcription Factors/genetics/metabolism
MH  - *Carcinoma, Hepatocellular/metabolism
MH  - Cell Line, Tumor
MH  - Gene Expression Regulation, Neoplastic
MH  - *Liver Neoplasms/metabolism
MH  - Mammals/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Thioredoxins/genetics/metabolism
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
OTO - NOTNLM
OT  - BTB and CNC homology 1
OT  - cancer stem cell
OT  - hepatocellular carcinoma
OT  - metastasis
OT  - thioredoxin
EDAT- 2023/04/27 18:41
MHDA- 2023/05/01 06:42
CRDT- 2023/04/27 12:32
PHST- 2023/04/14 00:00 [revised]
PHST- 2023/01/10 00:00 [received]
PHST- 2023/04/17 00:00 [accepted]
PHST- 2023/05/01 06:42 [medline]
PHST- 2023/04/27 18:41 [pubmed]
PHST- 2023/04/27 12:32 [entrez]
AID - 10.1096/fj.202300050RR [doi]
PST - ppublish
SO  - FASEB J. 2023 Jun;37(6):e22943. doi: 10.1096/fj.202300050RR.