Transgenic CHD1L expression in mouse induces spontaneous tumors.
BACKGROUND
Amplification of 1q21 is the most frequent genetic alteration in hepatocellular carcinoma (HCC), which was detected in 58-78% of primary HCC cases by comparative genomic hybridization (CGH). Using chromosome microdissection/hybrid selection approach we recently isolated a candidate oncogene CHD1L from 1q21 region. Our previous study has demonstrated that CHD1L had strong oncogenic ability, which could be effectively suppressed by siRNA against CHD1L. The molecular mechanism of CHD1L in tumorigenesis has been associated with its role in promoting cell proliferation.


RESULTS
To further investigate the in vivo oncogenic role of CHD1L, CHD1L ubiquitous-expression transgenic mouse model was generated. Spontaneous tumor formations were found in 10/41 (24.4%) transgenic mice, including 4 HCCs, but not in their 39 wild-type littermates. In addition, alcohol intoxication was used to induce hepatocyte pathological lesions and results found that overexpression of CHD1L in hepatocytes could promote tumor susceptibility in CHD1L-transgenic mice. To address the mechanism of CHD1L in promoting cell proliferation, DNA content between CHD1L-transgenic and wildtype mouse embryo fibroblasts (MEFs) was compared by flow cytometry. Flow cytometry results found that CHD1L could facilitate DNA synthesis and G1/S transition through the up-regulation of Cyclin A, Cyclin D1, Cyclin E, CDK2, and CDK4, and down-regulation of Rb, p27(Kip1), and p53.


CONCLUSIONS
Taken together, our data strongly support that CHD1L is a novel oncogene and plays an important role in HCC pathogenesis.
Chen
Muhan
M
Department of Clinical Oncology, The University of Hong Kong, Pokfulam, Hong Kong, China.
Huang
Jian-dong
JD
Hu
Liang
L
Zheng
Bo-jian
BJ
Chen
Leilei
L
Tsang
Sze Lan
SL
Guan
Xin-yuan
XY
D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D002874:Chromosome Mapping; D003043:Cocarcinogenesis; D004265:DNA Helicases / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D000431:Ethanol / Q000633:toxicity; D005434:Flow Cytometry; D015151:Immunoblotting; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D004268:DNA-Binding Proteins; D000431:Ethanol; D004265:DNA Helicases; C546393:Chd1l protein, mouse
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