Department of Medical Oncology, Yantaishan Hospital, Yantai, Shandong Province, China.
Department of Medical Oncology, Yantai Traditional Chinese Medicine Hospital, Yantai, Shandong Province, China.
Biochem Genet. 2024 Dec;62(6):4518-4535. doi: 10.1007/s10528-024-10682-z. Epub 2024 Feb 9.
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.
线粒体呼吸和代谢在促进癌细胞的迁移和侵袭能力方面起着关键作用。在这项研究中，我们旨在探讨糖蛋白 SPARC 对线粒体呼吸的潜在影响及其对肝癌（HCC）细胞迁移和侵袭的后续影响。我们使用慢病毒介导的 shRNA 递送来耗尽 HCC 细胞系中的 SPARC。通过细胞分级分离，然后进行 Western blot 分析、免疫荧光染色和蛋白酶 K 保护实验，验证了 SPARC 的线粒体定位。通过共免疫沉淀来研究 SPARC 和 GPD2 之间的相互作用。使用 Seahorse XF 细胞线粒体应激测试来评估 HCC 细胞的线粒体呼吸和功能。我们的研究确定了 HCC 细胞线粒体中 SPARC 的一个活跃池，线粒体亚群对于调节迁移和侵袭至关重要。线粒体 SPARC 与 GPD2 相互作用，影响其表达水平，并进而调节 GPD2 介导的线粒体呼吸。这种调节机制协调了 HCC 细胞的迁移和侵袭表型。值得注意的是，与正常肝组织相比，SPARC 和 GPD2 在 HCC 组织中表达上调。HCC 患者中 SPARC 和 GPD2 的高表达水平与预后较差相关。我们的研究揭示了 SPARC 在通过调节 GPD2 介导的线粒体呼吸来控制 HCC 细胞迁移和侵袭方面的新作用。这些发现强调了线粒体过程在癌症进展中的重要性，并提出了 SPARC/GPD2 轴作为 HCC 干预的有前途的靶点。
