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Investigation of oncogenic cooperation in simple liver-specific transgenic mouse models using noninvasive in vivo imaging.

ABSTRACT: Liver cancer is a complex multistep process requiring genetic alterations in multiple proto-oncogenes and tumor suppressor genes. Although hundreds of genes are known to play roles in hepatocarcinogenesis, oncogenic collaboration among these genes is still largely unknown. Here, we report a simple methodology by which oncogenic cooperation between cancer-related genes can be efficiently investigated in the liver. We developed various non-germline transgenic mouse models using hydrodynamics-based transfection which express HrasG12V, SmoM2, and a short-hairpin RNA down-regulating p53 (shp53) individually or in combination in the liver. In this transgenic system, firefly luciferase was co-expressed with the oncogenes as a reporter, allowing tumor growth in the liver to be monitored over time without an invasive procedure. Very strong bioluminescence imaging (BLI) signals were observed at 4 weeks post-hydrodynamic injection (PHI) in mice co-expressing HrasG12V and shp53, while only background signals were detected in other double or single transgenic groups until 30 weeks PHI. Consistent with the BLI data, tumors were observed in the HrasG12V plus shp53 group at 4 weeks PHI, while other transgenic groups failed to exhibit a hyperplastic nodule at 30 weeks PHI. In the HrasG12V plus shp53 transgenic group, BLI signals were well-correlated with actual tumor growth in the liver, confirming the versatility of BLI-based monitoring of tumor growth in this organ. The methodology described here is expected to accelerate and facilitate in vivo studies of the hepatocarcinogenic potential of cancer-related genes by means of oncogenic cooperation.

SUBMITTER: Ju HL

PROVIDER: S-EPMC3610734 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Investigation of oncogenic cooperation in simple liver-specific transgenic mouse models using noninvasive in vivo imaging.

Ju Hye-Lim HL Ahn Sang Hoon SH Kim Do Young DY Baek Sinhwa S Chung Sook In SI Seong Jinsil J Han Kwang-Hyub KH Ro Simon Weonsang SW

PloS one 20130328 3

Liver cancer is a complex multistep process requiring genetic alterations in multiple proto-oncogenes and tumor suppressor genes. Although hundreds of genes are known to play roles in hepatocarcinogenesis, oncogenic collaboration among these genes is still largely unknown. Here, we report a simple methodology by which oncogenic cooperation between cancer-related genes can be efficiently investigated in the liver. We developed various non-germline transgenic mouse models using hydrodynamics-based ...[more]

PMID: 23555816

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Project description:Background & aimsSome patients with nonalcoholic fatty liver disease (NAFLD) develop liver-related complications and have higher mortality than other patients with NAFLD. We determined the accuracy of simple, noninvasive scoring systems in identification of patients at increased risk for liver-related complications or death.MethodsWe performed a retrospective, international, multicenter cohort study of 320 patients diagnosed with NAFLD, based on liver biopsy analysis through 2002 and followed through 2011. Patients were assigned to mild-, intermediate-, or high-risk groups based on cutoff values for 2 of the following: NAFLD fibrosis score, aspartate aminotransferase/platelet ratio index, FIB-4 score, and BARD score. Outcomes included liver-related complications and death or liver transplantation. We used multivariate Cox proportional hazard regression analysis to adjust for relevant variables and calculate adjusted hazard ratios (aHRs).ResultsDuring a median follow-up period of 104.8 months (range, 3-317 months), 14% of patients developed liver-related events and 13% died or underwent liver transplantation. The aHRs for liver-related events in the intermediate-risk and high-risk groups, compared with the low-risk group, were 7.7 (95% confidence interval [CI]: 1.4-42.7) and 34.2 (95% CI: 6.5-180.1), respectively, based on NAFLD fibrosis score; 8.8 (95% CI: 1.1-67.3) and 20.9 (95% CI: 2.6-165.3) based on the aspartate aminotransferase/platelet ratio index; and 6.2 (95% CI: 1.4-27.2) and 6.6 (95% CI: 1.4-31.1) based on the BARD score. The aHRs for death or liver transplantation in the intermediate-risk and high-risk groups compared with the low-risk group were 4.2 (95% CI: 1.3-13.8) and 9.8 (95% CI: 2.7-35.3), respectively, based on the NAFLD fibrosis scores. Based on aspartate aminotransferase/platelet ratio index and FIB-4 score, only the high-risk group had a greater risk of death or liver transplantation (aHR = 3.1; 95% CI: 1.1-8.4 and aHR = 6.6; 95% CI: 2.3-20.4, respectively).ConclusionsSimple noninvasive scoring systems help identify patients with NAFLD who are at increased risk for liver-related complications or death. NAFLD fibrosis score appears to be the best indicator of patients at risk, based on HRs. The results of this study require external validation.

Dataset Information

Investigation of oncogenic cooperation in simple liver-specific transgenic mouse models using noninvasive in vivo imaging.

Publications

Investigation of oncogenic cooperation in simple liver-specific transgenic mouse models using noninvasive in vivo imaging.

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