APOBEC3G promotes liver metastasis in an orthotopic mouse model of colorectal cancer and predicts human hepatic metastasis
Qingqing Ding, … , Raymond N. DuBois, Mien-Chie Hung
Qingqing Ding, … , Raymond N. DuBois, Mien-Chie Hung
Published November 1, 2011; First published October 10, 2011
Citation Information: J Clin Invest. 2011;121(11):4526-4536. https://doi.org/10.1172/JCI45008.
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Research Article Oncology

APOBEC3G promotes liver metastasis in an orthotopic mouse model of colorectal cancer and predicts human hepatic metastasis

Abstract

Colorectal cancer is the second leading cause of death from cancer in the United States. Metastases in the liver, the most common metastatic site for colorectal cancer, are found in one-third of the patients who die of colorectal cancer. Currently, the genes and molecular mechanisms that are functionally critical in modulating colorectal cancer hepatic metastasis remain unclear. Here, we report our studies using functional selection in an orthotopic mouse model of colorectal cancer to identify a set of genes that play an important role in mediating colorectal cancer liver metastasis. These genes included APOBEC3G, CD133, LIPC, and S100P. Clinically, we found these genes to be highly expressed in a cohort of human hepatic metastasis and their primary colorectal tumors, suggesting that it might be possible to use these genes to predict the likelihood of hepatic metastasis. We have further revealed what we believe to be a novel mechanism in which APOBEC3G promotes colorectal cancer hepatic metastasis through inhibition of miR-29–mediated suppression of MMP2. Together, our data elucidate key factors and mechanisms involved in colorectal cancer liver metastasis, which could be potential targets for diagnosis and treatment.

Authors

Qingqing Ding, Chun-Ju Chang, Xiaoming Xie, Weiya Xia, Jer-Yen Yang, Shao-Chun Wang, Yan Wang, Jiahong Xia, Libo Chen, Changchun Cai, Huabin Li, Chia-Jui Yen, Hsu-Ping Kuo, Dung-Fang Lee, Jingyu Lang, Longfei Huo, Xiaoyun Cheng, Yun-Ju Chen, Chia-Wei Li, Long-Bin Jeng, Jennifer L. Hsu, Long-Yuan Li, Alai Tan, Steven A. Curley, Lee M. Ellis, Raymond N. DuBois, Mien-Chie Hung

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Figure 1

Identifying a gene expression signature for colorectal cancer liver metastasis.

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Identifying a gene expression signature for colorectal cancer liver meta...
(A) Flow chart of in vivo selection process of colorectal cancer cell metastasis to the liver. The nonmetastatic colorectal cancer cells (SW480) and those with only lymph node metastasis (SW620) were inoculated into the colon of nude mice. Liver tumors were detected by the IVIS Imaging System (Caliper Life Sciences), and tumor cells (L-1 and L-2) were then isolated from the liver lesions and reinoculated to confirm their metastatic phenotype. (B) Representative images of the liver metastases (upper panels) and IVIS luciferase images in mice inoculated with colorectal cancer cells (lower panels). The hepatic metastasis rate of colorectal cancer cells is indicated at the bottom. *P < 0.05; **P < 0.01 compared with SW480 and SW620 cells. (C) Representative immunohistochemistry staining of colorectal primary tumor and hepatic metastases from the orthotopic transplanted nude mice. Scale bars: 50 μm. (D) Gene expression profiles reveal a set of 68 genes that are highly expressed in L-1 and L-2 cells as compared with SW480 and SW620 cells. (E) Immunoblotting analysis of gene expression levels in SW480, SW620, L-1, and L-2 cells.