Identification of biomarkers associated with the development of hepatocellular carcinoma in CuZn superoxide dismutase deficient mice

Elchuri, Sailaja; Naeemuddin, Mohammed; Sharpe, Orr; Robinson, William H.; Huang, Ting‐Ting

doi:10.1002/pmic.200601011

Cited by 41 publications

(34 citation statements)

References 40 publications

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“…1). The decreased abundance of MUP in murine hepatocellular carcinoma (13) is similar to the findings in our study, possibly indicative of comparable pathological mechanisms in hepatocellular carcinoma and chronic schistosomiasis. Interest-ingly, the pattern of MUP isoforms differs between male and female mice (7), and this protein is similar to human epididymisspecific lipocalin 9 (30); whether lipocalin 9 correlates with degree of pathology in human schistosomiasis merits investigation.…”

Section: Discussionsupporting

confidence: 89%

Identification of Cytokeratin 18 as a Biomarker of Mouse and Human Hepatosplenic Schistosomiasis

et al. 2011

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Previously, we demonstrated unique protein expression patterns in 20-week-Schistosoma mansoni-infected CBA/J mice with moderate splenomegaly syndrome (MSS) or hypersplemomegaly syndrome (HSS). To better understand the development of severe pathology, we compared the two-dimensional differential in-gel electrophoresis (2D-DIGE) proteomic signatures of livers from uninfected mice and mice infected for 6, 8, 12, or 20 weeks and found significant changes in collagen isoforms, interleukin-2 (IL-2), cytokeratin 18, hydroxyproline, S. mansoni phosphoenolpyruvate carboxykinase, major urinary protein isoforms, and peroxiredoxin 6. Cytokeratin 18, hydroxyproline, and connective tissue growth factor (CTGF) were chosen for analysis in mouse and human sera using targeted biochemical assays. Consistent with the liver analysis, cytokeratin 18, CTGF, and hydroxyproline were significantly elevated in sera from mice with HSS compared to those from uninfected mice or mice with MSS. Moreover, cytokeratin 18 and CTGF were found to be markers for subjects with hepatosplenic and intestinal schistosomiasis, respectively, while serum hydroxyproline was a strong indicator of fibrosis for severe HS. These findings indicate that schistosome-associated changes to the liver can be detected in the serum and reveal the potential for cytokeratin 18 to be used as a diagnostic marker for early detection of hepatosplenic schistosomiasis.

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Section: Discussionsupporting

confidence: 89%

Identification of Cytokeratin 18 as a Biomarker of Mouse and Human Hepatosplenic Schistosomiasis

et al. 2011

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“…One of the most frequently used mouse models of oxidative stress and ageing is the copper-zinc Sod fully deficient mouse (Sod1 K/K ). Sod1 knockout animals (Sod1 K/K ) exhibit an elevation in the levels of various markers of oxidative stress (Elchuri et al 2005, Muller et al 2006, Perez et al 2009), but otherwise appear relatively normal under standard laboratory conditions (Reaume et al 1996, Elchuri et al 2007. The fertility of female Sod1 K/K mice is greatly reduced, but three independent studies have reported that males are fully fertile when mated with C57BL/6 females (Ho et al 1998, Matzuk et al 1998, Tsunoda et al 2012, the genetic background on which this knockout is usually maintained.…”

Section: Introductionmentioning

confidence: 99%

Copper-zinc superoxide dismutase deficiency impairs sperm motility and in vivo fertility

et al. 2013

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Oxidative stress, overproduction of reactive oxygen species (ROS) in relation to defence mechanisms, is considered to be a major cause of male infertility. For protection against the deleterious effects of ROS, animals have a variety of enzymatic antioxidants that reduce these molecules to less reactive forms. The physiological role of these antioxidants in vivo has been explored extensively through genetic inhibition of gene expression; surprisingly, many of these animals remain fertile in spite of increased oxidative stress. Copper-zinc superoxide dismutase-deficient (Sod1) male mice are one such example for which in vivo fertility has been repeatedly reported as normal, although examination of fertility has consisted of simply pairing animals of the same strain and checking for litters. This is a fairly low criterion by which to assess fertility. Herein, we show that Sod1-deficient males have zero fertilisation success in sperm competition trials that pit them against wild-type males of an otherwise identical genetic background and are almost completely infertile when mated singly with females of a different genotype. We also show that various aspects of sperm motility and function are impaired in Sod1-deficient mice. Testing the breeding capabilities of mice under more ecologically relevant conditions and with females of different genotypes may help reveal additional physiological causes of infertility.

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“…Of the three genes that encode SOD in mammals, SOD1 is present largely in the cytoplasm and partly in the intramembrane space of mitochondria (OkadoMatsumoto and Fridovich 2001). Among the multiple phenotypes, SOD1-knockout (KO) mice show a shortened life span with increasing incidence of hepatocarcinogenesis (Elchuri et al 2005;Busuttil et al 2005;Elchuri et al 2007) and abnormal lipid metabolism (Hadjur et al 2001;Uchiyama et al 2006;Wang et al 2012). The body weights of SOD1-KO mice are low compared to that of WT mice (Iuchi et al 2007), which is partly attributable to small amounts of visceral fats due to impaired lipid adsorption by the intestine (Kurahashi et al 2012).…”

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confidence: 99%

Oxidative stress caused by a SOD1 deficiency ameliorates thioacetamide-triggered cell death via CYP2E1 inhibition but stimulates liver steatosis

et al. 2016

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We investigated the responses of mice that are defective in the superoxide-scavenging enzyme SOD1 to thioacetamide (TAA)-induced hepatotoxicity. When a lethal dose of TAA (500 mg/kg) was intraperitoneally injected, the wild-type (WT) mice all died within 36 h, but all of the SOD1-knockout (KO) mice survived. Treatment with an SOD1 inhibitor rendered the WT mice resistant to TAA toxicity. To elucidate the mechanism responsible for this, we examined the acute effects of a sublethal dose of TAA (200 mg/kg) on the livers of WT and KO mice. The extent of TAA-induced liver damage was less in the KO mice, but, instead, lipogenesis was further advanced in the SOD1-KO livers. The levels of proteins modified with acetyllysine, a marker for TAA-mediated injury, were lower in the KO mice than the WT mice upon the TAA treatment. The KO mice, which were under oxidative stress per se, exhibited a lower CYP2E1 activity, and this appeared to result in a decrease in the production of reactive oxygen species (ROS) during TAA metabolism. Both cleaved ATF6, a transcriptional regulator that is activated by endoplasmic reticulum (ER) stress, and CHOP, a death signal mediator, were highly elevated in the WT mice as the result of the TAA treatment and consistent with the liver damage. We conclude that elevated TAA metabolites and reactive oxygen species that are produced by CYP-mediated drug metabolism trigger lipogenesis as well as liver damage via ER stress and determine the fate of the mice.

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Identification of biomarkers associated with the development of hepatocellular carcinoma in CuZn superoxide dismutase deficient mice

Cited by 41 publications

References 40 publications

Identification of Cytokeratin 18 as a Biomarker of Mouse and Human Hepatosplenic Schistosomiasis

Identification of Cytokeratin 18 as a Biomarker of Mouse and Human Hepatosplenic Schistosomiasis

Copper-zinc superoxide dismutase deficiency impairs sperm motility and in vivo fertility

Oxidative stress caused by a SOD1 deficiency ameliorates thioacetamide-triggered cell death via CYP2E1 inhibition but stimulates liver steatosis

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