Abstract
Despite numerous investigations on metastasis, the determinants of metastatic processes remain unclear. We aimed to identify the metastasis-associated genes in hepatocellular carcinoma (HCC). Potent metastatic SK-hep-1 (SK) cells, designated 'SKM', were generated using Transwell assay followed by selection in a mouse model. Genes expressed differentially in SKM and SK cells were identified via microarray analyses. A small form of Neural precursor cell-expressed developmentally downregulated 4 (sNEDD4) was identified to be overexpressed in SKM cells, which was confirmed as a novel transcript using liquid chromatography-mass spectrometry. In clinical specimens, sNEDD4 was significantly overexpressed in tumors and serves as a poor prognostic factor for male patients with HCC (P = 0.035). Upon subcutaneous introduction of sNEDD4-overexpressing SK cells into flanks of nude mice, tumors grew faster than those of the control group. Furthermore, sNEDD4-mediated promotion of tumor metastasis was demonstrated in the orthotopic mouse model. Overexpression of sNEDD4 increased the invasive ability of SK cells through upregulation of matrix metalloproteinase 9 and inhibited serum deprivation-induced apoptosis via upregulation of myeloid cell leukemia 1. In conclusion, sNEDD4 is a novel metastasis-associated gene, which prevents apoptosis under nutrient restriction conditions. The present findings clearly support the prognostic potential of sNEDD4 for HCC.
Highlights
Metastasis, the dissemination of cancer cells from the primary tumor and their colonization at a secondary site, is responsible for 90% of cancer-associated deaths
Our results showed that the invasion abilities of SKT and SKM cells are significantly increased, compared to that of SK parental cells (Figure 1B)
Species-specific incompatibility and manipulation in immunocompromised mouse, which eliminates the involvement of the immune system in tumor progression, are yet to be resolved, transplantation xenograft models remain the most prevalent model type to study human tumor metastasis
Summary
Metastasis, the dissemination of cancer cells from the primary tumor and their colonization at a secondary site, is responsible for 90% of cancer-associated deaths. It is a complex process with multiple steps comprising local invasion, intravasation, survival in the circulation, extravasation, and growth of metastases. Owing to the biological complexity of metastasis, no single model is sufficient to answer all our queries, and selection of an optimal model to clarify each biological process is necessary. An experimental metastasis model was utilized for selection of cells with highly metastatic properties. DNA microarray analyses comparing parental www.impactjournals.com/oncotarget cells with selected highly metastatic cells were subsequently performed to identify metastasis-associated genes
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