Role of diacylglycerol kinase delta in hepatocarcinogenesis

甘油二酯激酶（DGK）催化甘油二酯（DAG）磷酸化为磷脂酸（PA），在磷脂周转下游的信号转导中起重要作用。为了表征其肿瘤转化的作用，使用源自dgkd^<+/+>或dgkd^<+/->的小鼠胚胎成纤维细胞。与dgkd ^<+/+>细胞相比，dgkd ^<+/->细胞的生长受到严重抑制。与dgkd ^<+/+>细胞相比，Dgkd ^<+/->细胞对BrdU掺入的抑制降低了50%。与dgkd^<+/+>细胞相比，H-Ras和SV 40 T抗原诱导的dgkd^<+/->细胞的灶形成受到显著抑制。抗TGFα的中和抗体使dgkd^<+/+>细胞的病灶数量急剧减少到与dgkd^<+/->细胞相同的水平。半定量RT-PCR结果显示，人肝细胞癌（HCC）组织中DGKδ表达上调，HCC组织中TGFα的可溶性形式在血或尿中大量表达，而在非癌肝组织中表达上调。免疫组化结果显示，肝癌组织中DGKδ免疫反应强阳性的部位主要在门静脉附近或包膜下，TACE和TGFα在这些部位也有高表达，这些结果为DGKδ作用于肝癌的转化和发展提供了新的分子机制，并为肝癌的治疗提供了一个新的靶点。

Diacylglycerol kinases (DGKs), which catalyze phosphorylation of diacylglycerol (DAG) to phophatidic acid (PA), play an important role in the signal transduction downstream of phospholipid turnover. To characterize its role of neoplastic transformation, mouse embryonic fibroblasts derived from dgkd^<+/+> or dgkd^<+/-> were used. Dgkd^<+/-> cells were profoundly growth-inhibited versus dgkd^<+/+> cells. Dgkd^<+/-> cells showed a 50% decrease of inhibition of BrdU incorporation compared with dgkd^<+/+> cells. Foci formation of dgkd^<+/-> cells induced by H-Ras and SV40 T antigen was significantly suppressed when compared with that of dgkd^<+/+> cells. A neutralizing antibody to TGFα drastically reduced the number of foci of dgkd^<+/+> cells to the same level as that of dgkd^<+/-> cells. Semi-quantitative RT-PCR showed that DGKδ expression was upregulated in human hepatocellular carcinoma (HCC), in which a soluble form of TGFα was detected in large quantities in blood or urine, compared in non-cancerous liver tissues. Immunohistochemical study revealed that strong DGKδ-immunoreactivity was present at the leading edge of HCC, such as the site near portal vein or under the capsule of the tumor, in which high expression of TACE and TGFα was also detected.These observations provide a novel molecular mechanism of transformation and tumor progression via DGKδ action and a suitable therapeutic target in HCC.