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Updated: Aug 5, 2026
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
CACUL1 promotes hepatocellular carcinoma progression through enhanced tumor cell proliferation and
Xing Wang1, Yuhan Tan2, Ju Wang1
1Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Background:
Although cullin-family E3 ubiquitin ligases regulate diverse oncogenic pathways, the role of CACUL1 in hepatocellular carcinoma (HCC) remains poorly characterized.
Methods:
We performed pan-cancer expression and survival analysis using TCGA and GEO databases, validated findings through immunohistochemistry, and conducted functional studies in HCC cell lines using CRISPR-mediated CACUL1 knockout. Transcriptome sequencing, functional assays (CCK-8, wound-healing, transwell invasion), and single-cell RNA-sequencing were performed to elucidate mechanisms.
Results:
Pan-cancer analysis identified CACUL1 overexpression in HCC and gastric cancer (P < 0.001), with prognostic significance in 16 tumor types, including HCC (log-rank P < 0.01). CACUL1 expression independently predicted poor HCC prognosis (multivariable Cox, P < 0.05) and correlated with advanced clinicopathological features and reduced immune checkpoint expression. CACUL1 knockout inhibited HCC cell proliferation and migration but not invasion, with transcriptomic analysis revealing PI3K/AKT signaling pathway enrichment. Co-culture experiments demonstrated that CACUL1 promotes M2 macrophage polarization through Notch1 suppression, with pharmacological Notch inhibition phenocopying this effect.
Conclusion:
CACUL1 functions as a dual-axis oncogenic driver in HCC through enhanced tumor cell proliferation associated with PI3K/AKT signaling and immune evasion via Notch1-dependent macrophage polarization, positioning it as a candidate prognostic biomarker and therapeutic target.
