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Research Article
Shinji Tanaka
Tokyo Medical and Dental University
Corresponding Author
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Comprehensive analysis of clinical samples has recently identified molecular and immunological classification of hepatocellular carcinoma (HCC), and the CTNNB1 (β-catenin)-mutated subtype exhibits distinctive characteristics of immunosuppressive tumor microenvironment. For clarifying the molecular mechanisms, we first established human and mouse HCC cells with exon 3 skipping of β-catenin, which promoted nuclear translocation and activated the Wnt/β-catenin signaling pathway, by using newly developed multiplex CRISPR/Cas9-based genome engineering system. Gene set enrichment analysis indicated downregulation of immune-associated gene sets in the HCC cells with activated β-catenin signaling. T cell killing assays demonstrated that the mouse Ctnnb1Δex3 HCC cells evaded immune surveillance. Comparative analysis of gene expression profiles between HCC cells harboring wild-type and exon 3 skipping β-catenin elucidated that the expression levels of eight cytokines were commonly decreased in human and mouse β-catenin-mutated HCC cells. Public exome and transcriptome data of 373 human HCC samples showed significant downregulation of five candidate cytokine genes, CCL20, CXCL1, CXCL2, NAMPT and VEGFA, in HCC tumors with β-catenin hotspot mutations. Taken together, this study discovered that cytokine controlled by β-catenin signaling activation could contribute to immune evasion, and provided novel insights into cancer immunotherapy for the β-catenin-mutated HCC subtype.
Keywords
hepatocellular carcinoma (HCC), CTNNB1 , immunosuppressive tumor microenvironment, nuclear translocation
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No competing interests reported.
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CURRENT STATUS: Under Review
Version 1
Posted 10 Mar, 2021
No community comments so far
Editorial decision: Major revision
On 09 Apr, 2021
Reviews received
Received 21 Mar, 2021
Reviewers agreed
On 09 Mar, 2021
Reviewers invited
Invitations sent on 03 Mar, 2021
Editor assigned
On 03 Mar, 2021
Editor invited
On 03 Mar, 2021
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On 03 Mar, 2021
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On 21 Feb, 2021
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A new preprint design is coming!
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This preprint is under consideration at Scientific Reports. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Shinji Tanaka
Tokyo Medical and Dental University
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 10 Mar, 2021
No community comments so far
Editorial decision: Major revision
On 09 Apr, 2021
Reviews received
Received 21 Mar, 2021
Reviewers agreed
On 09 Mar, 2021
Reviewers invited
Invitations sent on 03 Mar, 2021
Editor assigned
On 03 Mar, 2021
Editor invited
On 03 Mar, 2021
Submission checks complete
On 03 Mar, 2021
First submitted
On 21 Feb, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Comprehensive analysis of clinical samples has recently identified molecular and immunological classification of hepatocellular carcinoma (HCC), and the CTNNB1 (β-catenin)-mutated subtype exhibits distinctive characteristics of immunosuppressive tumor microenvironment. For clarifying the molecular mechanisms, we first established human and mouse HCC cells with exon 3 skipping of β-catenin, which promoted nuclear translocation and activated the Wnt/β-catenin signaling pathway, by using newly developed multiplex CRISPR/Cas9-based genome engineering system. Gene set enrichment analysis indicated downregulation of immune-associated gene sets in the HCC cells with activated β-catenin signaling. T cell killing assays demonstrated that the mouse Ctnnb1Δex3 HCC cells evaded immune surveillance. Comparative analysis of gene expression profiles between HCC cells harboring wild-type and exon 3 skipping β-catenin elucidated that the expression levels of eight cytokines were commonly decreased in human and mouse β-catenin-mutated HCC cells. Public exome and transcriptome data of 373 human HCC samples showed significant downregulation of five candidate cytokine genes, CCL20, CXCL1, CXCL2, NAMPT and VEGFA, in HCC tumors with β-catenin hotspot mutations. Taken together, this study discovered that cytokine controlled by β-catenin signaling activation could contribute to immune evasion, and provided novel insights into cancer immunotherapy for the β-catenin-mutated HCC subtype.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
No competing interests reported.
This is a list of supplementary files associated with this preprint. Click to download.
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