ATORVASTATIN AND GENE EXPRESSION SIGNATURES IN HEPATOCARCINOGENESIS

Introduction and Objectives

Hepatocellular carcinoma (HCC) represents a significant global health burden as the fourth leading cause of cancer-related deaths. While statins have shown promise in HCC prevention, their molecular mechanisms remain poorly understood.

We investigated the effect of atorvastatin (AT) on gene expression profiles and hepatocarcinogenesis in a hexachlorobenzene (HCB)-induced HCC model.

Materials and Methods

Male Wistar rats were divided into four groups: control, AT (5 mg/kg), HCB (100 mg/kg), and AT+HCB. After 30 days of treatment, we analyzed hepatosomatic index, liver histology, and performed RNA sequencing to evaluate transcriptomic changes. Gene Set Enrichment Analysis and KEGG pathway analysis were used to identify key molecular pathways. Protein expression of selected targets was confirmed by immunohistochemistry.

Results

HCB treatment significantly increased hepatosomatic index (28%, p<0.01) and induced preneoplastic lesions, which were prevented by AT co-administration. RNA sequencing revealed HCB activated multiple oncogenic pathways, including RHO GTPase cycle, TGF-β, and receptor tyrosine kinase signaling, with 84.8% concordance with established cancer pathway genes. AT treatment upregulated protective PPAR signaling, autophagy, and cellular stress response pathways while downregulating oncogenic pathways activated by HCB. AT significantly reduced the expression of key oncogenic proteins including TGF-β1, p53, and c-Myc in HCB-treated liver tissue.

Conclusions

Atorvastatin effectively prevents HCB-induced hepatocarcinogenesis through multiple mechanisms, including modulation of key oncogenic pathways and promotion of protective cellular responses. These findings provide new insights into the molecular mechanisms of statin-mediated HCC prevention and identify potential therapeutic targets for future interventions.

Conflict of interest: Yes, National Council of Scientific and Technological Research (PIP GI-11220200100397CO), University of Buenos Aires (PID 20020170100278BA) and intramural Funds to the Clinical Cooperation Unit Healthy Metabolism, Medical Faculty Mannheim, Heidelberg University.