SPARC Controls Migration and Invasion of Hepatocellular Carcinoma Cells Via Regulating GPD2-Mediated Mitochondrial Respiration.

Mitochondrial respiration and metabolism play a pivotal role in facilitating the migratory and invasive capacities of cancer cells. In this study, we aimed to explore the potential influence of glycoprotein SPARC on mitochondrial respiration and its subsequent influence on the migration and invasion of hepatocellular carcinoma (HCC) cells. Lentivirus-mediated shRNA delivery was employed to deplete SPARC in HCC cell lines. The mitochondria localization of SPARC was validated using cellular fractionation followed by Western blot analysis, as well as immunofluorescence staining and Proteinase K protection assay. Co-immunoprecipitation was employed to investigate the interaction between SPARC and GPD2. Seahorse XF Cell Mito Stress Test was conducted to assess the mitochondrial respiration and functionality of HCC cells. Our study identifies an active pool of SPARC within the mitochondria of HCC cells, with the mitochondrial subset proving crucial for the regulation of migration and invasion. The mitochondrial SPARC interacts with GPD2, influencing its expression levels and subsequently modulating GPD2-mediated mitochondrial respiration. This regulatory mechanism orchestrates the migratory and invasive phenotypes of HCC cells. Notably, SPARC and GPD2 exhibit upregulated expression in HCC tissues compared to normal liver tissues. High expression levels of both SPARC and GPD2 in HCC patients are associated with a poorer prognosis. Our study unveils a novel role for SPARC in governing HCC cell migration and invasion through regulating GPD2-mediated mitochondrial respiration. These findings underscore the importance of mitochondrial processes in cancer progression and propose the SPARC/GPD2 axis as a promising target for HCC interventions.