PMID- 37877357
OWN - NLM
STAT- MEDLINE
DCOM- 20231031
LR  - 20231101
IS  - 2001-1326 (Electronic)
IS  - 2001-1326 (Linking)
VI  - 13
IP  - 10
DP  - 2023 Oct
TI  - N(6) -methyladenosine-modified circSTX6 promotes hepatocellular carcinoma 
      progression by regulating the HNRNPD/ATF3 axis and encoding a 144 amino acid 
      polypeptide.
PG  - e1451
LID - 10.1002/ctm2.1451 [doi]
LID - e1451
AB  - BACKGROUND: Circular RNAs (circRNAs) play a significant role in the initiation 
      and progression of various cancers, including hepatocellular carcinoma (HCC). 
      Circular syntaxin 6 (circSTX6, also known as hsa_circ_0007905) has been 
      identified as a microRNA (miRNA) sponge in pancreatic adenocarcinoma. However, 
      its full range of functions in terms of protein scaffold and translation remain 
      largely unexplored in the context of HCC. METHODS: The expression of circSTX6 and 
      its encoded protein was examined in HCC tumour tissues. N(6) -methyladenosine 
      (m(6) A) on circSTX6 was verified and quantified by methylated RNA 
      immunoprecipitation (Me-RIP), RIP and dual luciferase reporter assays. The 
      biological functions of circSTX6 and its encoded protein in HCC were clarified by 
      in vitro and in vivo experiments. Mechanistically, the interaction between 
      circSTX6 and heterogeneous nuclear ribonucleoprotein D (HNRNPD) was investigated 
      by RNA pull-down, RIP and fluorescence in situ hybridization (FISH)/IF. The 
      regulatory effects of circSTX6 and HNRNPD on activating transcription factor 3 
      (ATF3) mRNA were determined by mRNA stability and RIP assays. Furthermore, the 
      presence of circSTX6-encoded protein was verified by mass spectrometry. RESULTS: 
      CircSTX6 and its encoded 144 amino acid polypeptide, circSTX6-144aa, were highly 
      expressed in HCC tumour tissues and served as independent risk factors for 
      overall survival in HCC patients. The expression of circSTX6 was regulated by 
      METTL14 in an m(6) A-dependent manner. Functionally, circSTX6 accelerated HCC 
      proliferation and tumourigenicity and reinforced tumour metastasis in vitro and 
      in vivo. Mechanistically, circSTX6 acted as a sponge for HNRNPD protein, 
      facilitating its binding to ATF3 mRNA, consequently promoting ATF3 mRNA decay. 
      Meanwhile, circSTX6-144aa promoted HCC proliferation, migration and invasion 
      independent of circSTX6 itself. CONCLUSION: Collectively, our study reveals that 
      m(6) A-modified circSTX6 drives malignancy in HCC through the HNRNPD/ATF3 axis, 
      while its encoded circSTX6-144aa contributes to HCC progression independent of 
      circSTX6. CirSTX6 and its encoded protein hold promise as potential biomarkers 
      and therapeutic targets in HCC.
CI  - (c) 2023 The Authors. Clinical and Translational Medicine published by John Wiley & 
      Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
FAU - Lu, Jiahua
AU  - Lu J
AUID- ORCID: 0000-0002-6874-0123
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
FAU - Ru, Junnan
AU  - Ru J
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
FAU - Chen, Yunhao
AU  - Chen Y
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
AD  - Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang 
      University School of Medicine, Hangzhou, Peoples Republic of China.
FAU - Ling, Zhenan
AU  - Ling Z
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
FAU - Liu, Hanqing
AU  - Liu H
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
FAU - Ding, Bo
AU  - Ding B
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
FAU - Jiang, Yifan
AU  - Jiang Y
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
FAU - Ma, Jun
AU  - Ma J
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
FAU - Zhang, Deguo
AU  - Zhang D
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
FAU - Ge, Jiangzhen
AU  - Ge J
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
FAU - Li, Yu
AU  - Li Y
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
FAU - Sun, Fei
AU  - Sun F
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
FAU - Chen, Diyu
AU  - Chen D
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
FAU - Zheng, Shusen
AU  - Zheng S
AUID- ORCID: 0000-0003-1459-8261
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
FAU - Wu, Jian
AU  - Wu J
AD  - Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The 
      First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 
      Peoples Republic of China.
AD  - NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of the diagnosis and treatment of organ Transplantation, Research 
      Unit of Collaborative Diagnosis and Treatment For Hepatobiliary and Pancreatic 
      Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, Peoples 
      Republic of China.
AD  - Key Laboratory of Organ Transplantation, Research Center for Diagnosis and 
      Treatment of Hepatobiliary Diseases, Hangzhou, Zhejiang Province, Peoples 
      Republic of China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Transl Med
JT  - Clinical and translational medicine
JID - 101597971
RN  - 0 (Activating Transcription Factor 3)
RN  - 0 (Amino Acids)
RN  - 0 (ATF3 protein, human)
RN  - 0 (Heterogeneous-Nuclear Ribonucleoprotein D)
RN  - 0 (MicroRNAs)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Circular)
RN  - 0 (STX6 protein, human)
RN  - 0 (HNRNPD protein, human)
SB  - IM
MH  - Humans
MH  - *Activating Transcription Factor 3/genetics/metabolism
MH  - Amino Acids
MH  - *Carcinoma, Hepatocellular/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/genetics
MH  - *Heterogeneous-Nuclear Ribonucleoprotein D/genetics
MH  - In Situ Hybridization, Fluorescence
MH  - *Liver Neoplasms/metabolism
MH  - *MicroRNAs/genetics
MH  - RNA, Messenger
MH  - *RNA, Circular/genetics
PMC - PMC10599281
OTO - NOTNLM
OT  - N6-methyladenosine modification
OT  - RNA-binding protein
OT  - circRNA
OT  - hepatocellular carcinoma
OT  - mRNA decay
OT  - protein encoding
COIS- The authors declare that they have no competing interests.
EDAT- 2023/10/25 06:42
MHDA- 2023/10/26 06:42
PMCR- 2023/10/25
CRDT- 2023/10/25 05:43
PHST- 2023/09/24 00:00 [revised]
PHST- 2023/06/23 00:00 [received]
PHST- 2023/10/04 00:00 [accepted]
PHST- 2023/10/26 06:42 [medline]
PHST- 2023/10/25 06:42 [pubmed]
PHST- 2023/10/25 05:43 [entrez]
PHST- 2023/10/25 00:00 [pmc-release]
AID - CTM21451 [pii]
AID - 10.1002/ctm2.1451 [doi]
PST - ppublish
SO  - Clin Transl Med. 2023 Oct;13(10):e1451. doi: 10.1002/ctm2.1451.