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Extracellular matrix-growth factor signalling drives the oncogenic mir-125b-2/UCK2 axis in hepatocellular carcinoma
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DOI：10.1186/s41065-026-00673-y.png)
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Abstract
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Background Hepatocellular carcinoma (HCC) is characterized by coordinated transcriptional and post-transcriptional dysregulation. We sought to identify clinically relevant miRNA-mRNA regulatory axes with cross-cohort, multi-layer validation. Methods Tumor-normal differential expression was integrated across TCGA-LIHC and independent microarray cohorts. Predicted miRNA targets were filtered by inverse-direction overlap with consensus DEGs and evaluated for activity-abundance coherence and survival relevance. An eight-feature axis (four miRNAs and four target-set activities) was modeled using penalized Cox regression with cross-validation and externally validated. Results Four recurrent miRNAs were identified (miR-125b-2 downregulated; miR-21, miR-221, miR-9-1 upregulated). miR-125b-2 showed the strongest inverse coherence with its target set (rho = -0.41, P < 1 & times; 10(-)& sup1;& sup2;). The composite axis stratified TCGA overall survival (log-rank P < 0.0001) and validated in GSE31384 (HR = 1.62, 95% CI 1.15-2.28; C-index = 0.66). Seven targets met FDR <= 1%, with UCK2 exhibiting the strongest adverse association (HR = 2.78, P = 2.7 & times; 10(-)(9)). UCK2 was overexpressed, hypomethylated, enriched in epithelial compartments, and linked to proliferative and ECM/growth-factor signaling programs. Functional assays demonstrated that UCK2 knockdown suppressed proliferation, clonogenicity, and migration, whereas overexpression enhanced these phenotypes. Conclusions The miR-125b-2/UCK2 axis defines a metabolically driven, epithelial proliferative program coupled to ECM/GF signaling and represents a validated prognostic and biologically actionable node in HCC.
Keywords:
Hepatocellular carcinoma
miRNA/mRNA axis
Extracellular matrix signaling
Growth-factor circuits
Prognostic biomarkers
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