CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients
Leilei Chen, … , Yan Li, Xin-Yuan Guan
Leilei Chen, … , Yan Li, Xin-Yuan Guan
Published March 24, 2010
Citation Information: J Clin Invest. 2010;120(4):1178-1191. https://doi.org/10.1172/JCI40665.
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Research Article

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

Abstract

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.

Authors

Leilei Chen, Tim Hon Man Chan, Yun-Fei Yuan, Liang Hu, Jun Huang, Stephanie Ma, Jian Wang, Sui-Sui Dong, Kwan Ho Tang, Dan Xie, Yan Li, Xin-Yuan Guan

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Figure 9

Overexpression of CHD1L is associated with HCC metastases and decreased DFS time.

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Overexpression of CHD1L is associated with HCC metastases and decreased ...
(A) Example of CHD1L expression detected in a primary HCC tumor and its metastatic tumor, with markedly stronger CHD1L staining in the latter. (B) Kaplan-Meier DFS survival curve of HCC patients in correlation with CHD1L expression. The DFS rate significantly decreased in the subgroup of HCC patients with CHD1L overexpression (red line; n = 29) compared with the CHD1L-negative subgroup (blue line; n = 24). (C–E) IHC staining with anti-CHD1L antibody showed that higher CHD1L expression was often observed in tumor cells at the tumor edge (C), invading (arrows) to surrounding tissue (D, left and right) and blood vessels (E, left). The endothelial cells of blood vessels were stained by IHC with an anti-CD31 antibody on the serial section of a clinical sample (E, right). Original magnification, ×200 (A and C–E).