Steatosis induced by the accumulation of apolipoprotein A-I and elevated ROS levels in H-ras12V transgenic mice contributes to hepatic lesions

Wang, Aiguo; Moon, Hyung–Bae; Chae, Jung‐Il; Kim, Jin Man; Kim, Ye-Eun; Yu, Dae‐Yeul; Lee, Dong‐Seok

doi:10.1016/j.bbrc.2011.05.039

Cited by 11 publications

(8 citation statements)

References 30 publications

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“…4; supplemental Table S5). The elevation in ApoA1 protein levels and its accumulation around fatty vesicles has been previously reported by us (57), and the present data further confirmed these molecular events. Similarly, we previously reported the significant development of steatosis in transgenic mice expressing hepatitis C virus nonstructural 5A (NS5A) protein, and this was also primarily because of the accumulation of apolipoprotein A-I around fatty droplets (58).…”

Section: Discussionsupporting

confidence: 92%

Differential Proteomic Analysis of Gender-dependent Hepatic Tumorigenesis in Hras12V Transgenic Mice

Rong

Fan

et al. 2017

Molecular & Cellular Proteomics

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Male prevalence is an outstanding characteristic of hepatocellular carcinoma (HCC), and the underlying mechanisms for this have remained largely unknown. In the present study, Hras12V transgenic mice, in which hepatocyte-specific expression of the oncogene induces male-biased hepatic tumorigenesis, were studied, and altered proteins were detected by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Protein samples from hepatic tumor tissues (T) and peritumor tissues (P) of transgenic males and females and the corresponding normal liver tissues (Wt) of nontransgenic males and females were subjected to pairwise comparisons based on proteomic analysis. Among 2381 autodetected protein spots, more than 1600 were differentially expressed based on a pairwise comparison (|ratio|> = 1.5, < = 0.05). Of these, 180 spots were randomly selected for matrix-assisted laser desorption ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF MS) identification; finally, 89 distinct proteins were obtained. Among these 89 proteins, 7 and 50 proteins were further validated by Western blotting and literature investigation, respectively. Intriguingly, compared with Wt, the altered proteins were relatively concentrated in T in transgenic females but in P in transgenic males. Consistently, the levels of p-ERK and p-mTOR were significantly higher in the T of females compared with that of males. The pathway enrichment assay showed that 5 pathways in males but only 1 in females were significantly altered in terms of the upregulated proteins in T compared with Wt. These data indicate that female hepatocytes are disturbed by oncogenes with great difficulty, whereas male hepatocytes readily do so. In addition, 33 proteins were gender-dependently altered in hepatic tumorigenesis. Moreover, 4% DNA packaging and 4% homeostasis-related functional proteins were found in females but not in males, and more nucleus proteins were found in females (8%) than in males (3%). In conclusion, the proteomic data and comparative analysis presented here offer crucial clues for elucidating the mechanisms that underlie the male prevalence in HCC.

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Section: Discussionsupporting

confidence: 92%

Differential Proteomic Analysis of Gender-dependent Hepatic Tumorigenesis in Hras12V Transgenic Mice

Rong

Fan

et al. 2017

Molecular & Cellular Proteomics

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“…Thus, it is possible that the enhanced deposition of hepatic triglycerides and the deteriorated hepatic pathology and architecture observed in the apoA-I -/-mice in response to a high-fat diet could be due, at least in part, to the reduced LCAT activity of these mice. In a recent report (42), it was found that in H-ras12V transgenic mice with steatosis, apoA-I was elevated and accumulated around fatty vacuoles, leading these investigators to propose that apoA-I promotes steatosis. Our data allow for an alternative interpretation of those results, suggesting that the increased apoA-I presence around fat vacuoles may instead reflect a protective mechanism aimed at reducing the already elevated hepatic lipid content of H-ras12V transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein A-I Modulates Processes Associated with Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

Karavia

Papachristou

Liopeta

et al. 2012

Mol Med

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“…The male mice of this transgenic strain develop hepatocellular adenomas by 6 to 8 months followed by HCC at 9 months of age with high penetrance (>88%). Also, there is evidence for micro- and macrovesicular steatosis in both female and male mice (26). To investigate the roles of FoxM1 in HCC progression in that model, we generated a tri-transgenic strain that in addition to H-ras12V contained floxed alleles of FoxM1 and the MxCre gene.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies also indicated almost ubiquitous activation of the Ras-signaling pathway in hepatocellular carcinoma through silencing expression of the Ras regulatory GAP proteins (4). A transgenic mouse model that expresses H-ras12V in the liver was shown to develop steatosis, linking activated Ras-signaling to steatosis (26). Moreover, the male mice in that strain develop hepatocellular carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features

Kopanja

Pandey

Kiefer

et al. 2015

Journal of Hepatology

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Background & Aims Over-expression of FoxM1 correlates with poor prognosis in hepatocellular carcinoma (HCC). Moreover, the Ras-signaling pathway is found to be ubiquitously activated in HCC through epigenetic silencing of the Ras-regulators. We investigated the roles of FoxM1 in Ras-driven HCC, and on HCC cells with stem-like features. Methods We employed a transgenic mouse model that expresses the oncogenic Ras in the liver. That strain was crossed with a strain that harbor floxed alleles of FoxM1 and the MxCre gene that allows conditional deletion of FoxM1. FoxM1 alleles were deleted after development of HCC, and the effects on the tumors were analyzed. Also, FoxM1-siRNA was used in human HCC cell lines to determine its role in the survival of the HCC cells with stem cell features. Results Ras-driven tumors over-express FoxM1. Deletion of FoxM1 inhibits HCC progression. There was increased accumulation of reactive oxygen species (ROS) in the FoxM1-deleted HCC cells. Moreover, FoxM1-deletion caused a disproportionate loss of the CD44+ and EpCAM+ HCC cells in the tumors. We show that FoxM1 directly activates expression of CD44 in human HCC cells. Moreover, the human HCC cells with stem cell features are addicted to FoxM1 for ROS-regulation and survival. Conclusion Our results provide genetic evidence for an essential role of FoxM1 in the progression of Ras-driven HCC. In addition, FoxM1 is required for the expression of CD44 in HCC cells. Moreover, FoxM1 plays a critical role in the survival of the HCC cells with stem cell features by regulating ROS.

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Steatosis induced by the accumulation of apolipoprotein A-I and elevated ROS levels in H-ras12V transgenic mice contributes to hepatic lesions

Cited by 11 publications

References 30 publications

Differential Proteomic Analysis of Gender-dependent Hepatic Tumorigenesis in Hras12V Transgenic Mice

Differential Proteomic Analysis of Gender-dependent Hepatic Tumorigenesis in Hras12V Transgenic Mice

Apolipoprotein A-I Modulates Processes Associated with Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features

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