Role of diacylglycerol kinase delta in hepatocarcinogenesis

二酰甘油激酶δ在肝癌发生中的作用

• 批准号: 16591327
• 负责人: TAKETOMI Akinobu
• 金额: $ 2.18万
• 依托单位: KYUSHU UNIVERCITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591327/
• 关键词: diacylglycerol kinase; hepatocellular carcinoma; RT-PCR

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.

二酰基甘油激酶(DGKs)催化二酰基甘油(DAG)磷酸化为磷脂酸(PA)，在磷脂代谢下游的信号转导中起着重要作用。为了确定其在肿瘤转化中的作用，使用了来源于dgkd^&lt；+/+&gt；或dgkd^&lt；+/-&gt；的小鼠胚胎成纤维细胞。与Dgkd^&lt；+/+&gt；细胞相比，Dgkd^&lt；+/-&gt；细胞生长受到严重抑制。与Dgkd^&lt；+/+&gt；细胞相比，Dgkd^&lt；+/-&gt；细胞对BrdU掺入的抑制程度降低了50%。H-RAS和SV40T抗原诱导的dgkd^&lt；+/-&gt；细胞的病灶形成明显低于dgkd^&lt；+/+&gt；细胞。抗转化生长因子α的中和抗体可显著减少dgkd^&lt；+/+&gt；细胞的病灶数目，使其达到与dgkd^&lt；+/-&gt；细胞相同的水平。半定量逆转录聚合酶链式反应显示DGKδ在人肝细胞癌组织中表达上调，在血或尿液中检测到大量的可溶性转化生长因子α，而在非癌肝组织中表达上调。免疫组织化学研究显示，DGKδ在肝细胞癌前沿有较强的表达，如靠近门静脉的部位或肿瘤包膜下，也可检测到α的高表达，为DGKδ作用于肝细胞癌的转化和进展提供了新的分子机制和合适的治疗靶点。