Differential expression of key enzymes of energy metabolism in preneoplastic and neoplastic rat liver lesions induced by N-nitrosomorpholine and dehydroepiandrosterone

Mayer, Doris; Metzger, Christel; Leonetti, Paola; Beier, Konstantin; Benner, Axel; Bannasch, Peter

doi:10.1002/(sici)1097-0215(19980619)79:3<232::aid-ijc4>3.0.co;2-q

Cited by 28 publications

(21 citation statements)

References 24 publications

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“…Other proteins that have also been shown to be elevated in hepatocellular carcinoma include fibrinogen gamma chain precursor [30], glutathione S transferase [31], glycerol-3-phosphate dehydrogenase [32], histone-binding protein RBBP4 [33] and nucleophosmin [34]. Lamin-A/C was elevated in sera of patients with a hepatocellular carcinoma [35].…”

Section: Discussionmentioning

confidence: 98%

Proteomic Analysis of Differentially Expressed Proteins in Peripheral Cholangiocarcinoma

Darby

Vuillier-Devillers

Pinault

et al. 2010

Cancer Microenvironment

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Cholangiocarcinoma is an adenocarcinoma of the liver which has increased in incidence over the last thirty years to reach similar levels to other liver cancers. Diagnosis of this disease is usually late and prognosis is poor, therefore it is of great importance to identify novel candidate markers and potential early indicators of this disease as well as molecules that may be potential therapeutic targets. We have used a proteomic approach to identify differentially expressed proteins in peripheral cholangiocarcinoma cases and compared expression with paired non-tumoral liver tissue from the same patients. Two-dimensional fluorescence difference gel electrophoresis after labeling of the proteins with cyanines 3 and 5 was used to identify differentially expressed proteins. Overall, of the approximately 2,400 protein spots visualised in each gel, 172 protein spots showed significant differences in expression level between tumoral and non-tumoral tissue with p<0.01. Of these, 100 spots corresponding to 138 different proteins were identified by mass spectrometry: 70 proteins were over-expressed whereas 68 proteins were under-expressed in tumoral samples compared to nontumoral samples. Among the over-expressed proteins, immunohistochemistry studies confirmed an increased expression of 14-3-3 protein in tumoral cells while α-smooth muscle actin and periostin were shown to be overexpressed in the stromal myofibroblasts surrounding tumoral cells. α-Smooth muscle actin is a marker of myofibroblast differentiation and has been found to be a Ian A. Darby, Karine Vuillier-Devillers, and Émilie Pinault have equally contributed to this work.

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Section: Discussionmentioning

confidence: 98%

Proteomic Analysis of Differentially Expressed Proteins in Peripheral Cholangiocarcinoma

Darby

Vuillier-Devillers

Pinault

et al. 2010

Cancer Microenvironment

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“…However, in the estrogen-induced altered foci, the activities of G6Pase, ME, and SDH were reduced, and those of AP and COX were unchanged, whereas in amphophilic preneoplastic foci induced by DHEA these activities were found to be increased. 21 Thus, although the estrogen-induced altered liver acini and preneoplastic amphophilic foci produced by peroxisome proliferators share a distinct morphological appearance, they differ in important histochemical aspects. Moreover, the specific pattern of alterations of enzymic activities caused by intrahepatic transplantation of ovarian tissue does not resemble any pattern that has been observed in a model of hepatocarcinogenesis so far.…”

Section: Discussionmentioning

confidence: 99%

“…The following enzymes were investigated: glycogen synthase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphatase (G6Pase), glucose-6-phosphate dehydrogenase (G6PDH), pyruvate kinase (PK), succinate dehydrogenase (SDH), malic enzyme (ME), mitochondrial glycerol-3-phosphate dehydrogenase (mG3PDH), cytochrome c oxidase (COX), acid phosphatase (AP), and ␥-glutamyltransferase (GGT). [21][22][23][24] Furthermore, serial cryostat sections were stained for basophilia with toluidine blue, for the presence of neutral lipids with Fettrot B, and for the presence of glycogen with the PAS reaction.…”

Section: Histochemistry Of Enzymes and Metabolic Productsmentioning

confidence: 99%

Hepatocellular Alterations after Intraportal Transplantation of Ovarian Tissue in Ovariectomized Rats

Klotz

Hacker

Klingmüller

et al. 2000

The American Journal of Pathology

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The mechanisms of hepatocarcinogenesis by certain synthetic estrogens seem to involve both nongenotoxic and indirect genotoxic effects. However, the natural estrogen estradiol did not exert any carcinogenic effects in established experimental protocols. To elucidate specific long-term effects of natural estrogens on hepatocytes, small pieces of ovarian tissue were transplanted via the portal vein into the livers of ovariectomized female rats. One week, 3 weeks, and 3 months after transplantation the transplants were found to proliferate and to secrete estradiol. Three weeks after transplantation the hepatocytes of the liver acini downstream of the stimulated transplants already showed a remarkable loss of glycogen, distinct cytoplasmic amphophilia, enlargement of their nuclei, a strong increase in the number and size of peroxisomes, an increase in proliferative activity and apoptotic elimination, and changes in the activity of certain key enzymes of energy metabolism. All hepatocellular alterations could be inhibited by the estrogen receptor antagonist toremifene and are, therefore, attributed to specific effects of estradiol produced by the transplants. The observed alterations resemble in some respects amphophilic preneoplastic liver foci, which particularly occur after long-term administration of nongenotoxic hepatocarcinogens, including the adrenal steroid hormone dehydroepiandrosterone. In a preliminary experiment three of six animals exhibited a hepatocellular carcinoma, and another animal developed a hepatocellular adenoma 18 months after intrahepatic ovarian tissue transplantation. A causal relationship between the use of oral contraceptive steroids and the development of hepatocellular adenomas in humans is now accepted, whereas a definite relationship between oral contraceptive use and malignant liver tumors has not yet been established. Nevertheless, some authors reported an increase in incidence of hepatocellular carcinomas in women using hormonal contraceptives for prolonged periods. [1][2][3] This was supported by long-term animal studies, which demonstrate an enhancement of hepatocarcinogenesis by various synthetic estrogens, eg, ethinyl estradiol and diethylstilbestrol. 4 -7 The mechanisms of estrogen carcinogenesis are quite complex: They include nongenotoxic, ie, proliferative effects via direct mitogenic action, as well as by enhancement of the effects of epidermal growth factor (EGF), hepatocyte growth factor (HGF), and transforming growth factor ␣ (TGF␣) on hepatocytes. 8 -10 Furthermore, genotoxic effects like the formation of DNA adducts and the generation of reactive intermediates (quinones) and free radicals, causing lipid peroxidation, have been identified. 11,12 Interestingly, the natural estrogen estradiol exerts stimulating effects on hepatocyte proliferation, whereas no carcinogenic effect of estradiol has been demonstrated so far. 13 Some of the carcinogenic effects of ethinyl estradiol can be inhibited by simultaneous application of estrogen receptor antagonists like tamoxifen, ...

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“…Administration of the N-nitrosamine N-nitrosomorpholine (NNM) in rats is a well-examined model of chemically induced hepatocarcinogenesis (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Weber and Bannasch have used several dosage protocols of NNM administration (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Cocarcinogenic Effects of Islet Hormones and N-Nitrosomorpholine in Hepatocarcinogenesis after Intrahepatic Transplantation of Pancreatic Islets in Streptozotocin-Diabetic Rats

et al. 2005

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In contrast to high local insulin levels obtained after lownumber transplantation (n = 350) of islets of Langerhans into the livers of diabetic rats, low insulin levels after high-number transplantation (n = 1,000) do not suffice to induce hepatocarcinogenesis. Herein, we investigated the possible cocarcinogenic potential of high and, in particular, low insulin levels, combining this in vivo model with a chemical model of hepatocarcinogenesis after administration of Nnitrosomorpholine (NNM). In three main experiments, different schemes of single or continuous NNM administration were combined with different transplantation procedures in diabetic or nondiabetic animals, i.e., low-number and highnumber islet transplantation, transplantation of polystyrene particles, and sham transplantation. Animals were sacrificed between 3 and 53 weeks after transplantation procedures. Evidence for the cocarcinogenic effects of NNM and insulin was provided in each main experiment. NNM treatment after low-number islet transplantation resulted in an increase in the number of preneoplastic hepatocellular foci, and a significant increase in the number and an earlier appearance of hepatocellular adenomas and carcinomas compared with controls. Most intriguing was the increase in preneoplastic foci after combined NNM treatment and high-number islet transplantation, proving that insulin, even in lower doses, has at least cocarcinogenic effects on the downstream hepatocytes and thus promotes an otherwise initiated hepatocarcinogenic process. Conclusively, intrahepatic transplantation of pancreatic islets acts as a strong cocarcinogenic factor together with NNM in streptozotocin-diabetic rats. (Cancer Res 2005; 65(15): 7013-22)

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Differential expression of key enzymes of energy metabolism in preneoplastic and neoplastic rat liver lesions induced by N-nitrosomorpholine and dehydroepiandrosterone

Cited by 28 publications

References 24 publications

Proteomic Analysis of Differentially Expressed Proteins in Peripheral Cholangiocarcinoma

Proteomic Analysis of Differentially Expressed Proteins in Peripheral Cholangiocarcinoma

Hepatocellular Alterations after Intraportal Transplantation of Ovarian Tissue in Ovariectomized Rats

Cocarcinogenic Effects of Islet Hormones and N-Nitrosomorpholine in Hepatocarcinogenesis after Intrahepatic Transplantation of Pancreatic Islets in Streptozotocin-Diabetic Rats

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