CD44 upregulation in chronic liver disease marks the transition to hepatocellular carcinoma and portends poor prognosis

TL;DR

CD44 levels rise during chronic liver disease and are linked to liver cancer development and worse outcomes, making it a potential early marker and treatment target.

Contribution

CD44 is identified as a novel early biomarker for hepatocellular carcinoma progression from chronic liver disease.

Findings

CD44 and its isoforms v6 and v10 are progressively upregulated in chronic liver injury and HCC.

CD44high tumors are associated with poor survival and a protumor immune microenvironment in human HCC.

CD44 expression increases with fibrosis severity and is enriched in oncogenic pathways and immunosuppressive cells.

Abstract

Hepatocellular carcinoma (HCC) often arises from chronic liver disease, but early biomarkers of malignant transformation are lacking. CD44, a transmembrane glycoprotein with multiple isoforms, has been implicated in cancer progression and immune modulation.

We analysed CD44 expression in mouse models of chronic and acute liver injury and assessed its clinical relevance in human HCC using bulk and single-cell transcriptomic datasets.

CD44 and its isoforms v6 and v10 were progressively upregulated in chronic liver injury, peaking in HCC. CD44-positive hepatocytes increased with fibrosis severity and were abundant in murine liver tumours. In human HCC, CD44 expression was significantly elevated compared to non-tumorous liver and was associated with reduced overall survival. CD44high tumours showed enrichment in oncogenic signalling pathways and greater infiltration of immunosuppressive cells, including M2 macrophages and Th2 cells. Single-cell RNA-seq confirmed CD44 expression in both tumour and immune cells, linking it to a protumor immune microenvironment.

CD44 is a promising early biomarker of hepatocarcinogenesis and a potential therapeutic target. Its expression reflects disease progression from fibrosis to cancer and is associated with poor prognosis and immune evasion in HCC.

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