MSTO1 promotes hepatocellular carcinoma progression and represents a potential target for immunotherapy.

Abstract

The incidence of hepatocellular carcinoma (HCC) has increased over recent decades. While significant progress has been achieved in immunotherapy, the five-year survival rate is still unsatisfactory because of the low response rate and acquired resistance in a few patients, which reflects the complexity of the immune microenvironment in HCC. In this study, TCGA-LIHC, ICGC-LIRI-JP, and GEO data sets were used to verify the role of MSTO1 in the pathogenesis and progression of HCC. We then identified spatial distribution and cellular source of MSTO1 expression using single-cell RNA-sequencing and spatial transcriptomics. We investigated possible downstream mechanism of MSTO1 with virtual knockdown, DepMap, and scRNA-seq analysis. We evaluated the importance of MSTO1 for clinical treatment from the perspective of immune infiltration, cell-cell communication, immunotherapy databases, and orthotopic HCC model treated by AAV8-shMsto1. MSTO1 was upregulated in HCC and correlated with clinical features, including poor overall survival and advanced tumor stage. Functionally, MSTO1 promoted colony formation, migration, invasion, and in vivo progression of HCC. Mechanistically, HSP90AB1 was a potential downstream effector of MSTO1, related to MYC signaling pathway. Additional pathway analysis of the trajectories and metabolites revealed a correlation between the MSTO1+ malignant cells with MYC signaling, metabolic pathway, as well as an immunosuppressive microenvironment. MSTO1 knockdown and anti-PD-1 therapy might play a synergistic role in the treatment of HCC. Overall, MSTO1 plays an important role during the development of HCC, and it was also associated with survival or response to immunotherapy. The progression of HCC may be associated with HSP90AB1 and MYC, and targeting MSTO1 may effectively enhance the efficacy of anti-PD-1 therapy.