Key Takeaways & Executive Findings
- •• • CAR (NR1I3) is upregulated in 85% of HCC tumors, and its knockout reduces cell proliferation by 45% and migration by 60% (p < 0.001), indicating a direct oncogenic role. • • CAR directly binds to the ABCB1 promoter, increasing expression by 3.5-fold, which correlates with multidrug resistance and poor overall survival (hazard ratio = 2.3, p = 0.003). • • A 5-NR prognostic signature stratifies HCC patients into high- and low-risk groups with 5-year survival rates of 32% vs. 78% (p < 0.0001), outperforming traditional staging. • • Multi-omics analysis identified 12 NRs with >2-fold dysregulation (p < 0.01), providing a comprehensive landscape of NR alterations in HCC.
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with complex molecular heterogeneity limiting therapeutic efficacy. Nuclear receptors (NRs) are transcription factors that regulate key metabolic and proliferative pathways, yet their role in HCC progression is not fully elucidated. Here, we performed a comprehensive multi-omics analysis integrating transcriptomic, proteomic, and phosphoproteomic data from 120 HCC tumor and adjacent non-tumor tissues. We identified 28 NRs significantly dysregulated in tumors, with 12 showing >2-fold change (p < 0.01). Notably, constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2) were upregulated in 85% of tumors, correlating with poor overall survival (hazard ratio = 2.3, p = 0.003). Functional studies using CRISPR-Cas9 knockout in HCC cell lines demonstrated that CAR knockout reduced cell proliferation by 45% and migration by 60% (p < 0.001). Mechanistically, CAR directly bound to the promoter of the multidrug resistance gene ABCB1, increasing its expression by 3.5-fold. Furthermore, we developed a NR-based prognostic signature comprising 5 NRs that stratified patients into high- and low-risk groups with distinct 5-year survival rates (32% vs. 78%, p < 0.0001). Our findings reveal a critical role for NR signaling in HCC aggressiveness and drug resistance, and provide a novel prognostic tool. Targeting NRs, particularly CAR, may represent a promising therapeutic strategy for HCC.
1. Introduction
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related death globally, with a 5-year survival rate below 20% for advanced stages. Despite advances in surgical resection, liver transplantation, and systemic therapies, the molecular heterogeneity of HCC leads to frequent therapeutic resistance and relapse. Nuclear receptors (NRs) are ligand-activated transcription factors that regulate genes involved in metabolism, proliferation, and drug detoxification. Their aberrant expression has been implicated in various cancers, but their specific roles in HCC progression and drug resistance remain poorly understood. Existing studies have largely focused on individual NRs, lacking a systematic view of the NR signaling network in HCC.
To address this gap, we employed a multi-omics approach integrating transcriptomics, proteomics, and phosphoproteomics to profile NR expression and activity in a large cohort of HCC patients. We identified a core set of NRs that are consistently dysregulated and functionally validated their oncogenic roles. Our work not only uncovers a novel NR-based prognostic signature but also highlights CAR as a potential therapeutic target. This comprehensive analysis provides a foundation for developing targeted therapies and improving patient stratification in HCC.
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ZHANG Wei, LI Ming, WANG Fang, CHEN Jie, LIU Yang, ZHAO Lei, SUN Qian, ZHOU Hong (2025). Quantitative Analysis of Nuclear Receptor Signaling Pathways in Hepatocellular Carcinoma: A Multi-Omics Approach. Chinese Journal of New Drugs. https://doi.org/pub_80__articleID_234
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Frequently Asked Questions
What is the mechanistic basis for CAR's oncogenic effect in HCC?
CAR directly binds to the promoter of ABCB1, increasing its expression by 3.5-fold, which leads to enhanced drug efflux and multidrug resistance. Additionally, CAR knockout reduces cell proliferation by 45% and migration by 60%, indicating its role in tumor aggressiveness.
How does the 5-NR prognostic signature compare to traditional staging systems?
The signature stratifies patients into high- and low-risk groups with 5-year survival rates of 32% vs. 78% (p < 0.0001), which is more discriminative than the BCLC staging system in our cohort (C-index 0.82 vs. 0.71).
What are the potential off-target effects of targeting CAR in HCC therapy?
CAR is also involved in hepatic drug metabolism and energy homeostasis. Systemic CAR inhibition may lead to altered drug metabolism and metabolic disturbances. However, our data show that CAR knockout in HCC cells does not affect normal hepatocyte viability, suggesting a potential therapeutic window.
How were the 28 dysregulated NRs identified and validated?
We used RNA-seq and mass spectrometry to quantify NR expression and phosphorylation across 120 paired tumor/normal samples. Differential expression analysis with a fold-change threshold of >2 and p < 0.01 identified 28 NRs. Validation was performed by qRT-PCR and Western blot in an independent cohort of 50 patients.
What are the scalability and cost implications of implementing this multi-omics approach in clinical settings?
The multi-omics profiling costs approximately $1,500 per sample, which is higher than routine histopathology. However, the prognostic signature can be assessed by qRT-PCR of 5 NRs, costing less than $100 per sample, making it feasible for clinical adoption.
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