Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer
Myeloid Zinc Finger 1 Induces Migration, Invasion, and In vivo Metastasis through Axl Gene Expression in Solid Cancer
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DOI：
10.1158/1541-7786.mcr-09-0326
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发表时间：
2010-02-01
影响因子：
5.2
通讯作者：
Allgayer, Heike
中科院分区：
文献类型：
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作者：
Mudduluru, Giridhar;Vajkoczy, Peter;Allgayer, Heike
髓系锌指蛋白1(MZF1)是Scan结构域转录因子家族中的一员，通过高度保守的Scan基序形成二聚体。MZF1的沉默抑制了细胞的增殖，MZF1的异常表达导致肿瘤的发生。然而，MZF1在肿瘤转移中的潜在作用尚不清楚。AXL是一种受体酪氨酸激酶，首次被鉴定为慢性髓系白血病的转化基因。AXL过表达可诱导细胞增殖、迁移和侵袭，并在不同的人类肿瘤中高表达。在这项研究中，我们发现MZF1的过表达诱导了结直肠癌(RKO，SW480)和宫颈癌细胞(HeLa)的迁移和侵袭。此外，我们还发现MZF1与Ax1启动子结合，反式激活启动子活性，并以剂量依赖的方式增强Ax1-mRNA和蛋白的表达。体外实验中，下调Axl的sh-RNA可降低MZF1诱导的HeLa和RKO细胞的迁移和侵袭(P=0.05)。此外，在体内鸡胚胎转移实验中，过表达MZF1的RKO细胞显示出更多的肿瘤形成和肝转移。此外，MZF1和Ax1在切除的大肠肿瘤组织中的表达显著高于相应的正常组织(P=0.02；P=0.05)，且MZF1的表达与Ax1在肿瘤组织中的表达呈正相关(P<；0.01)。综上所述，这是第一个表明MZF1诱导结直肠癌和宫颈癌侵袭和体内转移的研究，至少部分是通过调节Ax1基因的表达来实现的。摩尔癌症资源；8(2)；159-69。(C)2010年AACR。
Myeloid zinc finger 1 (MZF1) is a member of the SCAN domain family transcription factors that form dimers through their highly conserved SCAN motifs. Silencing of MZF1 inhibits cell proliferation, and abnormal expression of MZF1 results in cancer development. However, a potential role of MZF1 in metastasis remains unclear. Axl is a receptor tyrosine kinase and was first identified as a transforming gene in chronic myeloid leukemia. Axl overexpression induces proliferation, migration, and invasion and is highly expressed in different human cancers. In this study, we show that overexpression of MZF1 induces migration and invasion in colorectal (Rko, SW480) and cervical (HeLa) cancer cells. In addition, we show that MZF1 binds to the Axl promoter, transactivates promoter activity, and enhances Axl-mRNA and protein expression in a dose-dependent manner. In vitro, sh-RNA knockdown of Axl reduced MZF1-induced migration and invasion in HeLa and Rko cells (P = 0.05). Additionally, Rko cells overexpressing MZF1 showed increased tumor formation and liver metastasis in the chicken-embryo-metastasis assay in vivo. Furthermore, the expression of MZF1 and Axl was significantly higher in resected colorectal tumors compared with corresponding normal tissues (P = 0.02; P = 0.05), and MZF1 expression was positively correlated with Axl gene expression in tumor tissues (P < 0.01). Taken together, this is the first study to show that MZF1 induces invasion and in vivo metastasis in colorectal and cervical cancer, at least in part by regulating Axl gene expression. Mol Cancer Res; 8(2); 159-69. (C) 2010 AACR.