Affiliation:
1. Division of Hepatobiliary and Pancreatic Surgery Department of Surgery The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Peoples Republic of China
2. NHC Key Laboratory of Combined Multi‐organ Transplantation Hangzhou Peoples Republic of China
3. 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
4. Key Laboratory of Organ Transplantation Research Center for Diagnosis and Treatment of Hepatobiliary Diseases Hangzhou Zhejiang Province Peoples Republic of China
5. Department of Thoracic Surgery The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou Peoples Republic of China
Abstract
AbstractBackgroundCircular 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.MethodsThe expression of circSTX6 and its encoded protein was examined in HCC tumour tissues. N6‐methyladenosine (m6A) 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.ResultsCircSTX6 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 m6A‐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.ConclusionCollectively, our study reveals that m6A‐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.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Zhejiang Province
Chinese Academy of Medical Sciences
Health Commission of Zhejiang Province
Subject
Molecular Medicine,Medicine (miscellaneous)
Cited by
9 articles.
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