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 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 5

APOBEC3G enhances colon cancer cell migration and invasion through restoration of MMP2 from the inhibition of miR-29.

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APOBEC3G enhances colon cancer cell migration and invasion through resto...
(A) Sequence alignment for miRNA-29 and its mRNA target MMP2 using TargetScan software. Square shows miR-29 consensus target sequence (left). Luciferase activity of pMIR-Report construct containing 3′ UTR of MMP2 miR-29 binding site was measured in 293 cells overexpressing miR-29 (right). *P < 0.05. (B) miR-29 and MMP2 mRNA levels in SW620 cells expressing miR-29 antagomir (si-miR-29) and L-1 cells expressing miR-29 precursor using quantitative PCR. (C) miR-29 and MMP2 mRNA levels in SW620 cells, L-1 cells expressing retroviral APOBEC-shRNA (si-APO) and si-miR-29 using quantitative PCR. (D) Immunoblotting was performed in L-1 cells knocking down APOBEC3G or miR-29 to examine mRNA and protein expression of the indicated genes. Wound healing assay was performed in (E) SW620 cells and (G) L-1 cells expressing the indicated constructs or oligonucleotides to measure cell migrating distance for 48 hours. The number of invasive cells was determined in (F) SW620 cells and (H) L-1 cells expressing the indicated constructs or oligonucleotides. Bars show the mean value of the representative results from 3 experiments, each conducted in duplicate (± SD).