CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients

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 immunoprecipi...

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Bibliographic Details
Published in:The Journal of clinical investigation 2010-04, Vol.120 (4), p.1178-1191
Main Authors: Chen, Leilei, Chan, Tim Hon Man, Yuan, Yun-Fei, Hu, Liang, Huang, Jun, Ma, Stephanie, Wang, Jian, Dong, Sui-Sui, Tang, Kwan Ho, Xie, Dan, Li, Yan, Guan, Xin-Yuan
Format: Article
Language:English
Subjects:
Animals
Binding sites
Biomedical research
Carcinoma, Hepatocellular - etiology
Carcinoma, Hepatocellular - pathology
cdc42 GTP-Binding Protein - metabolism
Cell Differentiation
Cell Line, Tumor
Cell Movement
Cloning
Development and progression
Disease Progression
DNA Helicases - physiology
DNA-Binding Proteins - physiology
Endothelial Cells - pathology
Female
Gene expression
Gene Expression Regulation, Neoplastic
Genes
Guanine Nucleotide Exchange Factors - genetics
Hepatoma
Humans
Liver cancer
Liver Neoplasms - etiology
Liver Neoplasms - pathology
Male
Medical prognosis
Mesoderm - pathology
Metastasis
Mice
Mice, SCID
Neoplasm Invasiveness
Neoplasm Metastasis
Oncogenes
Physiological aspects
Properties
Proteins
Rho Guanine Nucleotide Exchange Factors
Tumors
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Summary: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 immunoprecipitation-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-ARHGEF9-Cdc42-EMT might be a novel pathway involved in HCC progression and metastasis.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI40665