ANXA8 Down-regulation by EGF-FOXO4 Signaling Is Involved in Cell Scattering and Tumor Metastasis of Cholangiocarcinoma
ANXA8 Down-regulation by EGF-FOXO4 Signaling Is Involved in Cell Scattering and Tumor Metastasis of Cholangiocarcinoma
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DOI：
10.1053/j.gastro.2009.04.015
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发表时间：
2009-09-01
期刊：
影响因子：
29.4
通讯作者：
Kim, Dae-Ghon
中科院分区：
文献类型：
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作者：
Lee, Mi-Jin;Yu, Gyung-Ran;Kim, Dae-Ghon
背景与目的：胆管细胞癌中肉瘤样变有助于更具侵袭性的肝内扩散和广泛转移。因此，本研究的目的是确定CC在肿瘤进展和肉瘤样变过程中转移的分子机制。方法：采用消减抑制杂交(SSH)方法鉴定候选基因ANXA8和ANXA8的表达变化。肉瘤样CC细胞的表皮生长因子受体(EGFR)我们评估了。ANXA8在细胞和组织中的表达，并通过体外细胞实验和体内动物模型检测其功能意义。结果：ANXA8在人和仓鼠CCS中高表达，但随肿瘤去分化而下调。ANXA8在转录水平上受表皮生长因子(EGF)下调，这与CC细胞上皮向间充质转化(EMT)的形态变化有关。此外，异位的ANXA8逆转了细胞的形态，这与粘着斑激酶的表达和F-肌动蛋白动力学的改变有关。EGFR及其下游靶分子磷脂酰肌醇-3-激酶和Akt与FOXO4的磷酸化有关，从而抑制ANXA8的转录。此外，体外细胞侵袭实验和体内自发转移实验表明，ANXA8抑制CC细胞的迁移和转移特性。结论。这些发现提示FOXO4和ANXA8在生长因子介导的肿瘤进展和转移中起关键作用。
BACKGROUND & AIMS: The sarcomatoid change in cholangiocarcinoma (CC) contributes to more aggressive intrahepatic spread and widespread metastasis. Therefore, the aim of this study was to identify the molecular mechanisms of CC metastasis during tumor progression and sarcomatoid change. METHODS: Using the subtraction suppression hybridization (SSH) method, we identified altered expression of the candidate gene ANXA8 and. epidermal growth factor receptor (EGFR) in sarcomatoid CC cells. We assessed. ANXA8 expression during the progression of CC in cells and tissues and examined its functional significance by performing in vitro cell experiments and using in vivo animal models. RESULTS: ANXA8 is highly expressed in human and hamster CCs but is down-regulated with tumor dedifferentiation. ANXA8 is transcriptionally down-regulated by epidermal growth factor (EGF), which is correlated with the morphologic changes of the epithelial-to-mesenchymal transition (EMT) in the CC cells. Furthermore, ectopic ANXA8 reverses the morphology of cells, and this is associated with focal adhesion kinase expression and altered F-actin dynamics. EGFR and its downstream targets, phosphatidylinositol-3-kinase and Akt, are linked to the phosphorylation of FOXO4, which leads to the inhibition of ANXA8 transcription. In addition, an in vitro cell invasion assay and in vivo spontaneous metastasis assay reveal that ANXA8 inhibits the cell migratory and metastatic characteristics of CC cells. CONCLUSIONS. These findings suggest that FOXO4 and ANXA8 play key roles in growth factor-mediated tumor progression and metastasis during the EMT change in CC.