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Background <p>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.</p> Methods <p>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.</p> Results <p>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 (<i>ρ</i> = −0.41, <i>P</i> &lt; 1 × 10⁻¹²). The composite axis stratified TCGA overall survival (log-rank <i>P</i> &lt; 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, <i>P</i> = 2.7 × 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.</p> Conclusions <p>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.</p> Graphical Abstract <p></p>

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Extracellular matrix-growth factor signalling drives the oncogenic mir-125b-2/UCK2 axis in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月2日

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  • YunFeng Zhao,
  • HaoXin Shen,
  • Yibo Sun,
  • JinKun Song,
  • Chen GuangSun,
  • JinXiu Li,
  • HongYu Wang,
  • YinSen Song

摘要

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 (ρ = −0.41, P < 1 × 10⁻¹²). 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 × 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.

Graphical Abstract