Aspartyl-asparagyl β hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms
Aspartyl-asparagyl β hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms
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DOI：
10.1002/hep.21272
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发表时间：
2006-08-01
期刊：
影响因子：
13.5
通讯作者：
Wands, Jack R.
中科院分区：
文献类型：
--
作者：
Cantarini, M. Chiara;de la Monte, Suzanne M.;Wands, Jack R.
天冬氨酰-（天冬氨酰）-β-羟化酶（AAH）在各种恶性肿瘤中过表达，包括肝细胞癌（HCC）。AAH的上游调控及其在Notch介导的信号传导和HCC细胞运动中的功能作用被评估。采用实时定量RT-PCR和Western印迹分析，在15对HCC和邻近无HCC的人肝活检标本中测量AAH、胰岛素受体底物（IRS）、胰岛素和胰岛素样生长因子（IGF）受体和多肽、Notch、Jagged和HES的mRNA转录水平。相对于配对的无HCC肝组织，在87%的HCC中检测到AAH的过表达。IRS-1、IRS-2和IRS-4分别在80%的HCC样本中过表达，IGF-1和IGF-2受体分别在40%和100%的HCC中过表达。所有HCC样本的Notch-1和HES-1基因表达水平均相对升高。AAH的过表达导致Notch水平的增加，并且免疫共沉淀实验证明AAH和Notch以及其配体Jagged之间的直接相互作用。总之，HCC的恶性表型的贡献是由于IGF-I和IGF-II信号转导的激活，其导致AAH和Notch的过度表达。AAH在细胞运动性方面的功能作用与Notch信号通路的激活增加有关。
Aspartyl-(Asparagyl)-ss-hydroxylase (AAH) is overexpressed in various malignant neoplasms, including hepatocellular carcinomas (HCCs). The upstream regulation of AAH and its functional role in Notch-mediated signaling and motility in HCC cells was accessed. The mRNA transcript levels of AAH, insulin receptor substrate (IRS), insulin and insulin-like growth factor (IGF) receptors and polypeptides, Notch, Jagged, and HES were measured in 15 paired samples of HCC and adjacent HCC-free human liver biopsy specimens using real-time quantitative RT-PCR and Western blot analysis. Overexpression of AAH was detected in 87% of the HCC relative to the paired HCC-free liver tissue. IRS-1, IRS-2, and IRS-4 were each overexpressed in 80% of the HCC samples, and IGF-I and IGF-2 receptors were overexpressed in 40% and 100% of the HCCs, respectively. All HCC samples had relatively increased levels of Notch-1 and HES-1 gene expression. Overexpression of AAH led to increased levels of Notch, and co-immunoprecipitation experiments demonstrated a direct interaction between AAH and Notch as well as its ligand Jagged. In conclusion, contributions to the malignant phenotype of HCC is due to activation of IGF-I and IGF-II signaling that results in over-expression of both AAH and Notch. The functional role of AAH in relation to cell motility has been linked to increased activation of the Notch signaling pathway.