Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) is a global health challenge with high mortality. ATP6V1C1, one of the subunit genes of vacuolar adenosine triphosphatase (V-ATPase), is a potential oncogene. However, its role in HCC remains unclear. MATERIALS AND METHODS: Differential analysis of mRNA and microRNA (miRNA), combined with machine learning, identified ATP6V1C1 as a potential biomarker for HCC. The expression and prognostic role of ATP6V1C1 in HCC were evaluated. Additionally, we explored the distribution of ATP6V1C1 in HCC tumor microenvironment (TME) at single-cell and spatial transcriptome levels. Furthermore, the association between ATP6V1C1 and malignant biological features, TME characteristics, and therapy response in HCC was investigated. Finally, in vitro experiments validated the effects of ATP6V1C1 on the malignant phenotype of HCC. RESULTS: ATP6V1C1 had higher expression in HCC tissues compared to paired normal tissues. Upregulated ATP6V1C1 was associated with poor HCC prognosis. ATP6V1C1 was primarily expressed in malignant cells and the tumor region in HCC TME. A positive correlation was observed between ATP6V1C1 expression and the activation of cancer-related pathways. The high ATP6V1C1 expression group exhibited increased pro-tumorigenic immune infiltration, inhibited anti-tumor immune activity, and high tumor proliferation rate. HCC patients of low ATP6V1C1 expression group had more clinical response to anti-tumor therapies. Knockdown of ATP6V1C1 impaired the proliferation, migration, and invasion of HCC cells by downregulating the mTORC1 signaling pathway. CONCLUSION: ATP6V1C1 multifacetedly contributes to the oncogenesis and progression of HCC and is a promising diagnostic and prognostic biomarker with predictive value on therapy response.