Role of diacylglycerol kinase delta in hepatocarcinogenesis

二酰基甘油激酶（DGKs）催化二酰基甘油（DAG）磷酸化为磷脂酸（PA），在磷脂转化的下游信号转导中起重要作用。为了表征其在肿瘤转化中的作用，使用dgkd^<+/+>或dgkd^<+/->衍生的小鼠胚胎成纤维细胞。Dgkd^<+/->细胞与Dgkd^<+/ +>细胞相比，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SV40 T抗原诱导的dgkd^<+/->细胞的病灶形成明显受到抑制。TGFα中和抗体可将dgkd^<+/+>细胞的病灶数量急剧减少至与dgkd^<+/->细胞相同的水平。半定量RT-PCR显示，DGKδ在人肝细胞癌（HCC）中的表达上调，与非癌肝组织相比，在HCC中血液或尿液中检测到大量可溶性形式的TGFα。免疫组化研究显示，在HCC边缘，如门静脉附近或肿瘤包膜下，存在较强的dgk δ免疫反应性，TACE和TGFα也高表达。这些观察结果为通过DGKδ作用转化和肿瘤进展提供了一种新的分子机制，并为HCC提供了合适的治疗靶点。

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.