BRAP Promotes the Tumorigenesis of Hepatocellular Carcinoma by Corrupting Cancer Cell Cycle Regulation and Enhancing...

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.

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.

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.

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.