Integrated Bioinformatic and Experimental Analyses Identify CNTN6 as a Tumor-Promoting Factor and Prognostic Biomarker in Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) remains a highly lethal malignancy, and reliable biomarkers are needed for prognostic stratification and the development of therapeutic strategies. Contactin-6 (CNTN6), a member of the immunoglobulin superfamily of cell-adhesion molecules, has not been fully characterized in HCC. Methods: Public datasets were used to evaluate CNTN6 expression, clinicopathological associations, immune-cell infiltration, prognostic value, and correlations with drug sensitivity in HCC. The biological functions of CNTN6 were assessed using HCC cell lines and xenograft models with CNTN6 knockdown and overexpression. Results: CNTN6 was upregulated in HCC tissues and was associated with several clinicopathological features. Elevated CNTN6 expression was associated with poor survival outcomes and an M2-like macrophage infiltration signature. Functional enrichment analysis suggested that CNTN6-related proteins may participate in cell migration and oncogenic signaling pathways. In vitro, CNTN6 knockdown suppressed HCC cell proliferation, colony formation, migration, and invasion, whereas CNTN6 overexpression enhanced these malignant phenotypes. In vivo, CNTN6 knockdown reduced xenograft tumor growth and altered CD86/CD206 immunostaining patterns. Conclusions: CNTN6 is upregulated in HCC and may function as a tumor-promoting factor associated with poor prognosis and macrophage-related immune remodeling. Further mechanistic and clinical validation is warranted.