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已发表论文
BRAP 通过破坏癌细胞周期调控和增强免疫逃逸促进肝细胞癌的肿瘤发生
Authors Guo Y , Gu R , Gao F, Liu L, Deng D , Zhang Q , Wang L, Liu Q, Lan L , Cang S
Received 16 June 2025
Accepted for publication 22 November 2025
Published 16 December 2025 Volume 2025:12 Pages 2771—2793
DOI https://doi.org/10.2147/JHC.S547105
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Mohamed Shaker
Yan Guo,1,* Ruixue Gu,1,* Fangmiao Gao,1,* Lina Liu,1 Dongfeng Deng,2 Qinyu Zhang,1 Longhao Wang,1 Qinglin Liu,3 Ling Lan,4 Shundong Cang1
1Department of Oncology, Zhengzhou University People’s Hospital, Henan Provincial People’ s Hospital, Zhengzhou, Henan, People’s Republic of China; 2Department of Hepatobiliary surgery, Zhengzhou University People’s Hospital, Henan Provincial People’ s Hospital, Zhengzhou, Henan, People’s Republic of China; 3The First Clinical School, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, Hubei, People’s Republic of China; 4Department of Gastroenterology and Hepatology, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Ling Lan, Department of Gastroenterology and Hepatology, Zhengzhou University People’s Hospital, Zhengzhou, Henan Province, People’s Republic of China, Email lanling@zzu.edu.cn Shundong Cang, Department of Oncology, Zhengzhou University People’s Hospital, Zhengzhou, Henan Province, People’s Republic of China, Email shundongcang@zzu.edu.cn
Background: BRAP, a BRCA1-binding protein, exhibits elevated expression across multiple cancers and correlates with poor prognosis in hepatocellular carcinoma (HCC). However, its precise mechanistic roles in HCC tumorigenesis and immune landscape remodeling remain undefined.
Methods: BRAP expression levels and its diagnostic/prognostic value in HCC were analyzed using clinical HCC tissues and public datasets (TCGA and ICGC). CCK-8, colony formation, and EdU assays were employed to evaluate BRAP’s impact on HCC cell proliferation; these findings were further validated in vivo using CDX models. RNA-seq and TCGA data analyses were performed to identify BRAP-mediated cellular biological functions and potential underlying mechanisms, with further confirmed via flow cytometry and Western blotting. scRNA-seq data from the GEO and TCGA were used to assess correlations between BRAP expression and immune cell infiltration, as well as immune checkpoint genes (ICGs) expression in HCC. mfIHC, qRT‒PCR, and macrophage-tumor co-cultivation experiments were conducted to validate BRAP’s regulatory effects on immunosuppressive cell components in HCC.
Results: BRAP expression is significantly upregulated in HCC tissues and correlates with advanced pathological grades and poor patient prognosis. BRAP knockdown markedly reduced HCC cell proliferation both in vitro and in vivo; this anti-proliferative effect was achieved by inducing cell cycle arrest via suppression of the RAF/MEK/ERK signaling pathway. HCC cells with high BRAP expression exhibited increased infiltration of immunosuppressive cells, upregulated ICGs expression, and promoted M2 macrophage polarization.
Conclusion: BRAP drives HCC progression by promoting proliferation via RAF/MEK/ERK and shaping an immunosuppressive microenvironment. We identify BRAP as a novel prognostic biomarker and promising immunotherapeutic target in HCC.
Keywords: hepatocellular carcinoma, BRAP, immune evasion, cell cycle, MAPK/ERK pathway
1Department of Oncology, Zhengzhou University People’s Hospital, Henan Provincial People’ s Hospital, Zhengzhou, Henan, People’s Republic of China; 2Department of Hepatobiliary surgery, Zhengzhou University People’s Hospital, Henan Provincial People’ s Hospital, Zhengzhou, Henan, People’s Republic of China; 3The First Clinical School, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, Hubei, People’s Republic of China; 4Department of Gastroenterology and Hepatology, Zhengzhou University People’s Hospital, Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Ling Lan, Department of Gastroenterology and Hepatology, Zhengzhou University People’s Hospital, Zhengzhou, Henan Province, People’s Republic of China, Email lanling@zzu.edu.cn Shundong Cang, Department of Oncology, Zhengzhou University People’s Hospital, Zhengzhou, Henan Province, People’s Republic of China, Email shundongcang@zzu.edu.cn
Background: BRAP, a BRCA1-binding protein, exhibits elevated expression across multiple cancers and correlates with poor prognosis in hepatocellular carcinoma (HCC). However, its precise mechanistic roles in HCC tumorigenesis and immune landscape remodeling remain undefined.
Methods: BRAP expression levels and its diagnostic/prognostic value in HCC were analyzed using clinical HCC tissues and public datasets (TCGA and ICGC). CCK-8, colony formation, and EdU assays were employed to evaluate BRAP’s impact on HCC cell proliferation; these findings were further validated in vivo using CDX models. RNA-seq and TCGA data analyses were performed to identify BRAP-mediated cellular biological functions and potential underlying mechanisms, with further confirmed via flow cytometry and Western blotting. scRNA-seq data from the GEO and TCGA were used to assess correlations between BRAP expression and immune cell infiltration, as well as immune checkpoint genes (ICGs) expression in HCC. mfIHC, qRT‒PCR, and macrophage-tumor co-cultivation experiments were conducted to validate BRAP’s regulatory effects on immunosuppressive cell components in HCC.
Results: BRAP expression is significantly upregulated in HCC tissues and correlates with advanced pathological grades and poor patient prognosis. BRAP knockdown markedly reduced HCC cell proliferation both in vitro and in vivo; this anti-proliferative effect was achieved by inducing cell cycle arrest via suppression of the RAF/MEK/ERK signaling pathway. HCC cells with high BRAP expression exhibited increased infiltration of immunosuppressive cells, upregulated ICGs expression, and promoted M2 macrophage polarization.
Conclusion: BRAP drives HCC progression by promoting proliferation via RAF/MEK/ERK and shaping an immunosuppressive microenvironment. We identify BRAP as a novel prognostic biomarker and promising immunotherapeutic target in HCC.
Keywords: hepatocellular carcinoma, BRAP, immune evasion, cell cycle, MAPK/ERK pathway