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The MBNL3 splicing factor promotes hepatocellular carcinoma by increasing PXN expression through the alternative splicing of lncRNA-PXN-AS1
Abstract
Understanding the roles of splicing factors and splicing events during tumorigenesis would open new avenues for targeted therapies. Here we identify an oncofetal splicing factor, MBNL3, which promotes tumorigenesis and indicates poor prognosis of hepatocellular carcinoma patients. MBNL3 knockdown almost completely abolishes hepatocellular carcinoma tumorigenesis. Transcriptomic analysis revealed that MBNL3 induces lncRNA-PXN-AS1 exon 4 inclusion. The transcript lacking exon 4 binds to coding sequences of PXN mRNA, causes dissociation of translation elongation factors from PXN mRNA, and thereby inhibits PXN mRNA translation. In contrast, the transcript containing exon 4 preferentially binds to the 3' untranslated region of PXN mRNA, protects PXN mRNA from microRNA-24-AGO2 complex-induced degradation, and thereby increases PXN expression. Through inducing exon 4 inclusion, MBNL3 upregulates PXN, which mediates the pro-tumorigenic roles of MBNL3. Collectively, these data demonstrate detailed mechanistic links between an oncofetal splicing factor, a splicing event and tumorigenesis, and establish splicing factors and splicing events as potential therapeutic targets.
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“the upregulation of MBNL3, which encodes for a splicing factor highly expressed in both fetal livers and in HCC, was associated with the reactivation of an upstream SE (Supplementary Fig. 4d)59.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [59]
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Metadata
- Authors
- Yuan, J.-H., Liu, X.-N., Wang, T.-T., Pan, W., Tao, Q.-F., Zhou, W.-P., Wang, F., & Sun, S.-H.
- Affiliations
- Second Military Medical University (CN)
- Corresponding author
- Wang, Fang
- Venue
- Nature Cell Biology
- Published
- 2017-05-29
- Volume
- 19
- Issue
- 7
- Pages
- 820-832
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2618859545
- Cited by
- 367
- References
- 59
- Citations by year
- 2026: 13 · 2025: 22 · 2024: 45 · 2023: 50 · 2022: 54 · 2021: 55 · 2020: 39 · 2019: 49 · 2018: 34 · 2017: 6
- FWCI
- 14.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Science Foundation of Shanghai
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
- Keywords
- hepatocellular carcinoma, alternative splicing, mRNA translation repression, mRNA degradation, 3' untranslated region, carcinogenesis, prognosis, therapeutic target
- MeSH terms
- Nanog Homeobox Protein, Animals, Binding Sites, Carrier Proteins, Exons, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Mice, Inbred C57BL, Mice, Nude, Protein Binding, Time Factors, Transfection, Up-Regulation, Gene Expression Regulation, Neoplastic, RNA-Binding Proteins, Alternative Splicing, 3' Untranslated Regions, Gene Expression Profiling, RNA Interference, MicroRNAs, Tumor Burden, Cell Proliferation, Octamer Transcription Factor-3, Mice, Paxillin, SOXB1 Transcription Factors, Hep G2 Cells, High-Throughput Nucleotide Sequencing, Argonaute Proteins, RNA, Long Noncoding
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