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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

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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 7

Silencing CHD1L expression inhibits its invasive and tumorigenic ability.

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Silencing CHD1L expression inhibits its invasive and tumorigenic ability...
(A) Compared with Con-8024 cells, CHD1L and ARHGEF9 expression decreased in shCHD1L-1–8024 and shCHD1L-2–8024 cells, as detected by qPCR. (B) Expression of Cdc42-GTP and total Cdc42 was detected by Western blot analysis. β-Actin was used as a loading control. (C) Expression of CHD1L, E-cadherin, β-catenin, N-cadherin, and vimentin was compared among 3 cell lines by Western blotting and quantified by densitometry (normalized to β-actin). (D) Representative images showing decreased formation of filopodia (arrows), increased expression of E-cadherin, and decreased expression of vimentin in shCHD1L-1–8024 and shCHD1L-2–8024 cells compared with Con-8024 cells. Nuclei were counterstained with DAPI. (E) Number of cells that invaded through the Matrigel was counted in 10 fields under the ×20 objective lens. (F) Reduced tumor volume or absent tumor formation was observed in mice injected with shCHD1L-8024 cells. (G) The mean volume of tumors induced by Con-8024 cells was significantly larger than that induced by shCHD1L-8024 cells on the sixth week after injection (n = 6). (H) IHC staining for E-cadherin and vimentin on serial sections of tumors induced by Con-8024 and shCHD1L-8024. Original magnification, ×400 (D and H).

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