Decreased ID2 promotes metastatic potentials of hepatocellular carcinoma by altering secretion of vascular endothelial growth factor
Decreased ID2 promotes metastatic potentials of hepatocellular carcinoma by altering secretion of vascular endothelial growth factor
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DOI：
10.1158/1078-0432.ccr-07-1116
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发表时间：
2008-02-15
影响因子：
11.5
通讯作者：
Oka, Masaaki
中科院分区：
文献类型：
--
作者：
Tsunedomi, Ryouichi;Iizuka, Norio;Oka, Masaaki
目的：目的探讨DNA结合/分化抑制因子2（Inhibitor of DNA binding/differentiation 2，ID2）在肝细胞癌（HCC）门静脉浸润中的分子生物学功能。为了阐明ID2的确切作用，我们用表达载体和小干扰RNA进行了体外分析。分别采用Matrigel包被的侵袭小室、ELISA和Western blot分析ID2对细胞侵袭能力以及血管内皮生长因子（VEGF）和缺氧诱导因子-1 α表达的影响。ID2 mRNA水平与门静脉浸润呈负相关（P <0.001）、肿瘤淋巴结转移分期（P <0.001）、肿瘤大小（P <0.001）、早期肝内复发（P <0.05）。当仅限于丙型肝炎病毒相关的HCC队列时，ID2水平低的患者的无病生存时间明显短于ID2水平高的患者。转染ID2表达载体的细胞侵袭能力低于空载体转染的细胞。过表达ID 2的细胞还表现出VEGF分泌和缺氧诱导因子-1 α蛋白水平下降。ID2敲低实验的结果是相反的ID2过表达experiments.Conclusions：在我们的临床和体外数据的基础上，我们建议，ID2在肝癌进展过程中的转移过程中发挥了重要作用。这一行动可能是解释，至少部分是由于VEGF分泌减少改变细胞的流动性。
Purpose: We aimed to explore the molecular and biological functions of Inhibitor of DNA binding/differentiation 2 (ID2), which was found to be responsible for portal vein invasion of hepatocellular carcinoma (HCC).Experimental Design: We measured ID2 m RNA levels in 92 HCC patients by real-time reverse transcription-PCR and examined the relation to clinicopathologic features. To clarify the precise roles of ID2, we did in vitro analysis with expression vectors and small interfering RNAs. Effects of ID2 on cell invasive potential and expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha were analyzed by Matrigel-coated invasion chamber, ELISA, and Western blot analysis, respectively.Results: ID2 mRNA level correlated inversely with portal vein invasion (P < 0.001), tumor-node-metastasis stage (P < 0.001), tumor size (P < 0,001), and early intrahepatic recurrence (P < 0.05). When limited to a cohort of hepatitis C virus-related HCCs, patients with low levels of ID2 had significantly shorter disease-free survival time than those with high levels of ID2. Invasive potential of cells transfected with ID2 expression vector was lower than that of empty vector - transfected cells. Cells overexpressing ID2 also showed decreased VEGF secretion and hypoxia-inducible factor-1 alpha protein levels. The results of ID2-knockdown experiments were opposite to those of ID2 overexpression experiments.Conclusions: On the basis of our clinical and in vitro data, we suggest that ID2 plays a significant role in the metastatic process during progression of HCC. This action might be explained, at least in part, by altered cell mobility due to decreased secretion of VEGF.