CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients
CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients
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CHD1L 促进小鼠肝细胞癌的进展和转移，并与人类患者的这些过程相关
DOI：
10.1172/jci40665
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发表时间：
2010-04-01
影响因子：
15.9
通讯作者：
Guan, Xin-Yuan
中科院分区：
文献类型：
--
作者：
Chen, Leilei;Chan, Tim Hon Man;Guan, Xin-Yuan
染色体结构域解旋酶/ATP酶DNA结合蛋白1样基因（Chromodomain helicase/ATP酶DNA binding protein 1-like gene，CHD 1 L）是最近发现的一个癌基因，位于肝细胞癌（hepatocellular carcinoma，HCC）中扩增频率较高的1 q21区域。为了探索其致癌机制，我们开始在人肝癌细胞系中使用基于染色质免疫沉淀（ChIP）的克隆策略来鉴定CHD 1 L调控的基因。然后，我们进一步表征了1个已鉴定的基因ARHGEF 9，其编码Rho小GTdR Cdc 42的特异性鸟嘌呤核苷酸交换因子（GEF）。ARHGEF 9的过表达在分析的大约一半的人HCC样品中检测到，并且与CHD 1 L过表达呈正相关。在体外和在小鼠体内的功能研究表明，CHD 1 L有助于肿瘤细胞的迁移，侵袭和转移，通过增加细胞运动性和诱导丝状伪足形成和上皮间质转化（EMT）通过ARHGEF 9介导的Cdc 42激活。通过RNAi沉默ARHGEF 9表达有效地消除了CHD 1 L在小鼠中的侵袭和转移能力。此外，对临床HCC标本的研究表明，与健康组织相比，CHD 1 L和ARHGEF 9在转移性HCC组织中显著过表达。CHD 1 L的表达增加常出现在HCC肿瘤的浸润前沿，并与静脉浸润、微卫星肿瘤结节形成和无病生存率低相关。提示CHD 1 L-RHGEF 9-Cdc 42-EMT可能是参与HCC进展和转移的一条新途径。
Chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is a recently identified oncogene localized at 1q21, a frequently amplified region in hepatocellular carcinoma (HCC). To explore its oncogenic mechanisms, we set out to identify CHD1L-regulated genes using a chromatin itnmunoprecipitation-based (ChIP-based) cloning strategy in a human HCC cell line. We then further characterized 1 identified gene, ARHGEF9, which encodes a specific guanine nucleotide exchange factor (GEF) for the Rho small GTPase Cdc42. Overexpression of ARHGEF9 was detected in approximately half the human HCC samples analyzed and positively correlated with CHD1L overexpression. In vitro and in vivo functional studies in mice showed that CHD1L contributed to tumor cell migration, invasion, and metastasis by increasing cell motility and inducing filopodia formation and epithelial-mesenchymal transition (EMT) via ARHGEF9-mediated Cdc42 activation. Silencing ARHGEF9 expression by RNAi effectively abolished the invasive and metastatic abilities of CHD1L in mice. Furthermore, investigation of clinical HCC specimens showed that CHD1L and ARHGEF9 were markedly overexpressed in metastatic HCC tissue compared with healthy tissue. Increased expression of CHD1L was often observed at the invasive front of HCC tumors and correlated with venous infiltration, microsatellite tumor nodule formation, and poor disease-free survival. These findings suggest that CHD1L-RHGEF9-Cdc42-EMT might be a novel pathway involved in HCC progression and metastasis.