In Silico Profiling of Cytokine Signatures in Hepatocellular Carcinoma Reveals Elevated CXCL9/10 and Reduced IL-10 Expression

Hepatocellular carcinoma (HCC) arises within a pro-inflammatory microenvironment where cytokines and chemokines significantly influence tumor development and immune response. This study aimed to identify specific immunoregulatory alterations associated with malignant transformation in HCC by analyzing transcriptomic differences in cytokine and chemokine gene expression between tumor and adjacent non-tumor liver tissues.

An in silico transcriptomic analysis was conducted using the publicly available RNA-seq dataset GSE124535, which includes 73 paired HCC (tumor, T) and adjacent non-tumor (P) liver samples. Expression levels (FPKM) of 13 cytokine and chemokine genes, IL1B, TNF, IL6, IL10, IL1RN, TGFB1, CCL2, CXCL8, CXCL9, CXCL10, IFNG, IFNA1, and IFNB1, were quantified and transformed using log₂(FPKM+1). Statistical significance of differential expression was evaluated using Mann–Whitney U tests and Welch’s t-tests. Principal component analysis (PCA) was applied to Z-score–normalized cytokine expression data.

CXCL10 expression was significantly elevated in HCC samples compared to non-tumor tissue (mean log₂[FPKM+1]: 4.35 vs. 3.15; p = 1.3×10⁻³, Wilcoxon; p = 9.6×10⁻⁴, t-test), alongside a moderate increase in CXCL9 (3.30 vs. 2.58; p ≈ 3.0×10⁻² and 2.2×10⁻²). In contrast, IL-10 expression was significantly decreased in tumor tissue (0.31 vs. 0.78; p = 2.9×10⁻⁴ and 7.9×10⁻⁵). Other cytokines did not exhibit statistically significant differences. PCA revealed partial separation between tumor and non-tumor samples, with PC1 and PC2 explaining 32% and 18% of total variance, respectively.

The observed cytokine expression profile in HCC suggests a shift toward enhanced chemotactic signaling, particularly via CXCL9 and CXCL10, coupled with reduced anti-inflammatory regulation through IL-10. This altered cytokine landscape may influence tumor immune evasion and shape the tumor microenvironment, highlighting the importance of these mediators in disease progression.

HCC is associated with a distinctive cytokine signature characterized by the upregulation of chemokines CXCL9 and CXCL10 and downregulation of IL-10. These findings indicate that CXCL9 and CXCL10 may serve as promising diagnostic and prognostic biomarkers, while IL-10 represents a potential therapeutic target for modulating the immune response in HCC.