Intrinsic activation of β-catenin signaling by CRISPR/Cas9-mediated exon skipping contributes to immune evasion in hepatocellular carcinoma
Abstract 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 mo...
Guardado en:
| Autores principales: | , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/63c7a6b15ee74a9d819e44b8f20fa851 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:63c7a6b15ee74a9d819e44b8f20fa851 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:63c7a6b15ee74a9d819e44b8f20fa8512021-12-02T19:02:30ZIntrinsic activation of β-catenin signaling by CRISPR/Cas9-mediated exon skipping contributes to immune evasion in hepatocellular carcinoma10.1038/s41598-021-96167-02045-2322https://doaj.org/article/63c7a6b15ee74a9d819e44b8f20fa8512021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-96167-0https://doaj.org/toc/2045-2322Abstract 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. Comparative analysis of gene expression profiles between HCC cells harboring wild-type and exon 3 skipping β-catenin elucidated that the expression levels of four 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 two candidate cytokine genes, CCL20 and CXCL2, in HCC tumors with β-catenin hotspot mutations. T cell killing assays and immunohistochemical analysis of grafted tumor tissues demonstrated that the mouse Ctnnb1 Δex3 HCC cells evaded immunosurveillance. 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.Masafumi AkasuShu ShimadaAyano KabashimaYoshimitsu AkiyamaMasahiro ShimokawaKeiichi AkahoshiAtsushi KudoShoji YamaokaMinoru TanabeShinji TanakaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Masafumi Akasu Shu Shimada Ayano Kabashima Yoshimitsu Akiyama Masahiro Shimokawa Keiichi Akahoshi Atsushi Kudo Shoji Yamaoka Minoru Tanabe Shinji Tanaka Intrinsic activation of β-catenin signaling by CRISPR/Cas9-mediated exon skipping contributes to immune evasion in hepatocellular carcinoma |
| description |
Abstract 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. Comparative analysis of gene expression profiles between HCC cells harboring wild-type and exon 3 skipping β-catenin elucidated that the expression levels of four 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 two candidate cytokine genes, CCL20 and CXCL2, in HCC tumors with β-catenin hotspot mutations. T cell killing assays and immunohistochemical analysis of grafted tumor tissues demonstrated that the mouse Ctnnb1 Δex3 HCC cells evaded immunosurveillance. 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. |
| format |
article |
| author |
Masafumi Akasu Shu Shimada Ayano Kabashima Yoshimitsu Akiyama Masahiro Shimokawa Keiichi Akahoshi Atsushi Kudo Shoji Yamaoka Minoru Tanabe Shinji Tanaka |
| author_facet |
Masafumi Akasu Shu Shimada Ayano Kabashima Yoshimitsu Akiyama Masahiro Shimokawa Keiichi Akahoshi Atsushi Kudo Shoji Yamaoka Minoru Tanabe Shinji Tanaka |
| author_sort |
Masafumi Akasu |
| title |
Intrinsic activation of β-catenin signaling by CRISPR/Cas9-mediated exon skipping contributes to immune evasion in hepatocellular carcinoma |
| title_short |
Intrinsic activation of β-catenin signaling by CRISPR/Cas9-mediated exon skipping contributes to immune evasion in hepatocellular carcinoma |
| title_full |
Intrinsic activation of β-catenin signaling by CRISPR/Cas9-mediated exon skipping contributes to immune evasion in hepatocellular carcinoma |
| title_fullStr |
Intrinsic activation of β-catenin signaling by CRISPR/Cas9-mediated exon skipping contributes to immune evasion in hepatocellular carcinoma |
| title_full_unstemmed |
Intrinsic activation of β-catenin signaling by CRISPR/Cas9-mediated exon skipping contributes to immune evasion in hepatocellular carcinoma |
| title_sort |
intrinsic activation of β-catenin signaling by crispr/cas9-mediated exon skipping contributes to immune evasion in hepatocellular carcinoma |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/63c7a6b15ee74a9d819e44b8f20fa851 |
| work_keys_str_mv |
AT masafumiakasu intrinsicactivationofbcateninsignalingbycrisprcas9mediatedexonskippingcontributestoimmuneevasioninhepatocellularcarcinoma AT shushimada intrinsicactivationofbcateninsignalingbycrisprcas9mediatedexonskippingcontributestoimmuneevasioninhepatocellularcarcinoma AT ayanokabashima intrinsicactivationofbcateninsignalingbycrisprcas9mediatedexonskippingcontributestoimmuneevasioninhepatocellularcarcinoma AT yoshimitsuakiyama intrinsicactivationofbcateninsignalingbycrisprcas9mediatedexonskippingcontributestoimmuneevasioninhepatocellularcarcinoma AT masahiroshimokawa intrinsicactivationofbcateninsignalingbycrisprcas9mediatedexonskippingcontributestoimmuneevasioninhepatocellularcarcinoma AT keiichiakahoshi intrinsicactivationofbcateninsignalingbycrisprcas9mediatedexonskippingcontributestoimmuneevasioninhepatocellularcarcinoma AT atsushikudo intrinsicactivationofbcateninsignalingbycrisprcas9mediatedexonskippingcontributestoimmuneevasioninhepatocellularcarcinoma AT shojiyamaoka intrinsicactivationofbcateninsignalingbycrisprcas9mediatedexonskippingcontributestoimmuneevasioninhepatocellularcarcinoma AT minorutanabe intrinsicactivationofbcateninsignalingbycrisprcas9mediatedexonskippingcontributestoimmuneevasioninhepatocellularcarcinoma AT shinjitanaka intrinsicactivationofbcateninsignalingbycrisprcas9mediatedexonskippingcontributestoimmuneevasioninhepatocellularcarcinoma |
| _version_ |
1718377268425785344 |