Rac1 promotes diethylnitrosamine (DEN)-induced formation of liver tumors.

Abstract:

:To elucidate the function of the Ras-homologous GTPase Rac1 in hepatocarcinogenesis induced by diethylnitrosamine (DEN), mice lacking hepatic Rac1 expression were treated with DEN and compared to the wild-type (WT). Rac1 knock-out (KO) mice were found to have a lower tumor yield as compared to Rac1 proficient mice. The small-sized tumors formed in the absence of Rac1 lack an activated Ras/Raf/mitogen-activated protein kinase pathway, as indicated by the absence of p-ERK expression. Apparently, Rac1 is required for Ras-driven oncogenic pathways. Moreover, tumors in Rac1 deficient mice were glutamine synthase (GS) negative. They displayed a high number of p-H3-positive and cyclinB1 expressing cells, pointing to a defect in mitotic progression. To elucidate the influence of Rac1 on mechanisms of tumor initiation, acute DEN-induced hepatic stress responses were monitored. Rac1 deficiency caused fairly complex, partially time-dependent, alterations in both basal and/or DEN-induced messenger RNA (mRNA) and protein levels of susceptibility-related genes. Basal protein expression of DNA repair factors Brca1 and DNA repair protein RAD51 homolog (Rad51) and the cell cycle regulatory factor p27 was enhanced in the absence of Rac1. Following DEN treatment, p21 mRNA and protein expression was stimulated independent of the Rac1 status. Lack of Rac1 increased mechanisms of the DNA damage response (DDR), as shown by elevated protein levels of p-ATR, p-p53 and γH2AX 24h after DEN treatment. The data show that Rac1 is essential for DEN-stimulated hepatocarcinogenesis. We hypothesize that it promotes tumor initiation by counteracting the elimination of initiated cells and, moreover, alleviates the outgrowth of transformed cells. Hence, pharmacological targeting of Rac1 could be suitable for chemoprevention.

journal_name

Carcinogenesis

journal_title

Carcinogenesis

authors

Bopp A,Wartlick F,Henninger C,Schwarz M,Kaina B,Fritz G

doi

10.1093/carcin/bgu323

subject

Has Abstract

pub_date

2015-03-01 00:00:00

pages

378-89

issue

3

eissn

0143-3334

issn

1460-2180

pii

bgu323

journal_volume

36

pub_type

杂志文章
  • Absence of regular alpha2(I) collagen chains in colon carcinoma biopsy fragments.

    abstract::The extracellular matrix (ECM) is known to play an active role in numerous biological processes such as differentiation, apoptosis and cancer. Extensive alterations of epithelial basement membranes and of interstitial ECM are known to occur during the progression of most invasive carcinomas. Collagen, which represents...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/19.4.575

    authors: Pucci-Minafra I,Andriolo M,Basiricò L,Alessandro R,Luparello C,Buccellato C,Garbelli R,Minafra S

    更新日期:1998-04-01 00:00:00

  • The prolyl isomerase Pin1 interacts with a ribosomal protein S6 kinase to enhance insulin-induced AP-1 activity and cellular transformation.

    abstract::Phosphorylation of proteins on serine or threonine residues that immediately precede proline (pSer/Thr-Pro) is specifically catalyzed by the peptidyl-prolyl cis-trans isomerase Pin1 and is a central signaling mechanism in cell proliferation and transformation. Although Pin1 is frequently overexpressed in hepatocellula...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgp027

    authors: Lee NY,Choi HK,Shim JH,Kang KW,Dong Z,Choi HS

    更新日期:2009-04-01 00:00:00

  • Delayed expression of apoptotic and cell-cycle control genes in carcinogen-exposed bladders of mice lacking p53.S389 phosphorylation.

    abstract::Mice with non-phosphorylated serine 389 in p53 are susceptible for bladder tumors induced by 2-acetylaminofluorene (2-AAF). Since p53 is a transcription factor, this might well be preceded by differences in the regulation of gene expression. Microarray analysis was used to determine early transcriptional changes that ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgm041

    authors: Bruins W,Jonker MJ,Bruning O,Pennings JL,Schaap MM,Hoogervorst EM,van Steeg H,Breit TM,de Vries A

    更新日期:2007-08-01 00:00:00

  • Resistance of DRH strain rats to chemical carcinogenesis of liver: genetic analysis of later progression stage.

    abstract::The inbred DRH rats are highly resistant to the induction of hepatocellular carcinoma (HCC) by feeding of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB). Previously, we found that two quantitative trait loci (QTLs), Drh1 and Drh2, significantly reduced the number, size and area of glutathione S-transferase-placental ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/23.1.189

    authors: Yan Y,Zeng ZZ,Higashi S,Denda A,Konishi Y,Onishi S,Ueno H,Higashi K,Hiai H

    更新日期:2002-01-01 00:00:00

  • NF-kappaB inhibition radiosensitizes Ki-Ras-transformed cells to ionizing radiation.

    abstract::Most cancer cells show resistance to ionizing radiation (IR)-induced cell death. Recently, Ki-Ras was reported to be responsible for the increased radioresistance. We report here that inhibition of IR-induced activaton of nuclear transcription factor kappa B (NF-kappaB) but not of either Akt or MAPK kinase (MEK), incr...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgi081

    authors: Kim BY,Kim KA,Kwon O,Kim SO,Kim MS,Kim BS,Oh WK,Kim GD,Jung M,Ahn JS

    更新日期:2005-08-01 00:00:00

  • DNA adducts, detected by 32P-postlabelling, in DNA treated in vitro with bile from patients with familial adenomatous polyposis and from unaffected controls.

    abstract::Patients with familial adenomatous polyposis (FAP) have a high risk of developing duodenal adenomas and carcinomas. The distribution of these neoplasms resembles mucosal exposure to bile, suggesting that bile may play a role in adenoma development. Our previous results, using DNA adducts detected by 32P-postlabelling ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/14.6.1107

    authors: Scates DK,Spigelman AD,Nugent KP,Phillips RK,Venitt S

    更新日期:1993-06-01 00:00:00

  • Fez1/Lzts1-deficient mice are more susceptible to N-butyl-N-(4-hydroxybutil) nitrosamine (BBN) carcinogenesis.

    abstract::FEZ1/LZTS1 is a tumor suppressor gene that is frequently altered in human cancers of different histotypes. We have reported previously that LZTS1 is downregulated in high-grade bladder cancer and that its restoration suppresses tumorigenicity in urothelial carcinoma cells. To further investigate the role of LZTS1 in t...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgn006

    authors: Baffa R,Fassan M,Sevignani C,Vecchione A,Ishii H,Giarnieri E,Iozzo RV,Gomella LG,Croce CM

    更新日期:2008-04-01 00:00:00

  • Composition and turnover of phospholipids and neutral lipids in human breast cancer and reference tissues.

    abstract::The phospholipid (PL) content was 4-fold higher while the triacylglycerol (TG) content tended to be 65% lower in human breast cancer tissues as compared with non-cancerous reference parts from excised breast tissues. The variation in TG content among breast tissues was very large while that of PL was relatively small....

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/13.4.579

    authors: Sakai K,Okuyama H,Yura J,Takeyama H,Shinagawa N,Tsuruga N,Kato K,Miura K,Kawase K,Tsujimura T

    更新日期:1992-04-01 00:00:00

  • Reduction of immunosuppression in UV-irradiated mice by dietary retinyl palmitate plus canthaxanthin.

    abstract::The ability of dietary retinyl palmitate, canthaxanthin or the combination of both, to prevent induction of immunosuppression by UVB irradiation was tested by passive transfer of splenocytes. The basal diet was the American Institute of Nutrition diet 76A, containing 4 IU retinyl palmitate/g diet. Groups of 55 mice we...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/10.1.203

    authors: Gensler HL

    更新日期:1989-01-01 00:00:00

  • Deficiency of C-C chemokine receptor 5 suppresses tumor development via inactivation of NF-κB and inhibition of monocyte chemoattractant protein-1 in urethane-induced lung tumor model.

    abstract::To evaluate the significance of C-C chemokine receptor type 5 (CCR5) in lung tumor development, we compared carcinogen-induced tumor growth in CCR5 knockout (CCR5(-/-)) mice and wild-type (CCR5(+/+)) mice. CCR5(-/-) mice showed reduced urethane (1g/kg)-induced tumor incidence when compared with those of CCR5(+/+) mice...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgs265

    authors: Lee NJ,Choi DY,Song JK,Jung YY,Kim DH,Kim TM,Kim DJ,Kwon SM,Kim KB,Choi KE,Moon DC,Kim Y,Han SB,Hong JT

    更新日期:2012-12-01 00:00:00

  • Effects of ethinyl estradiol and tamoxifen on liver DNA turnover and new synthesis and appearance of gamma glutamyl transpeptidase-positive foci in female rats.

    abstract::We investigated possible mechanisms associated with promotion of hepatocarcinogenesis by the synthetic estrogens mestranol (M) and ethinyl estradiol (EE). Our first objective was to determine whether chronic EE treatment was associated with hepatotoxicity accompanied by regenerative hyperplasia. Female Sprague-Dawley ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/7.12.2007

    authors: Yager JD,Roebuck BD,Paluszcyk TL,Memoli VA

    更新日期:1986-12-01 00:00:00

  • Characterization and properties of the DNA adducts formed from N-methyl-4-aminoazobenzene in rats during a carcinogenic treatment regimen.

    abstract::Chronic oral administration of the carcinogenic aminoazo dye N-methyl-4-aminoazobenzene (MAB) to rats is known to result in the induction of liver tumors. In order to assess the role of carcinogen-DNA adduct formation in MAB hepatocarcinogenesis, male rats were fed 0.06% [3'-3H]MAB in the diet for 1, 3 or 5 weeks. Gro...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/8.4.577

    authors: Tullis DL,Dooley KL,Miller DW,Baetcke KP,Kadlubar FF

    更新日期:1987-04-01 00:00:00

  • Nafenopin-induced rat liver peroxisome proliferation reduces DNA methylation by N-nitrosodimethylamine in vivo.

    abstract::The hypolipidaemic drug nafenopin (NAF) has been shown to enhance the hepatocarcinogenic effect of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine in rats. We have investigated whether the NAF-induced peroxisome proliferation in hepatocytes interferes with NDMA's metabolism and interaction with DNA. Adult male...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/6.9.1309

    authors: Wiestler OD,Schmerold I,Fringes B,Volk B,Kleihues P

    更新日期:1985-09-01 00:00:00

  • Correlation between morphology and blood group-related antigen expression in pancreatic tumors induced in Syrian hamsters.

    abstract::Expression of blood group-related antigens (BGRAs) A, B, H, Le(b), Le(x) and Le(y) was examined immunohistochemically in neoplastic and hyperplastic lesions induced by N-nitrosobis(2-oxopropyl)amine in Syrian hamsters to determine a relationship between histological and biological patterns of the lesion and expression...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/12.3.441

    authors: Tomioka T,Fujii H,Egami H,Takiyama Y,Pour PM

    更新日期:1991-03-01 00:00:00

  • Risk of genome-wide association study-identified genetic variants for non-Hodgkin lymphoma in a Chinese population.

    abstract::Recent genome-wide association studies have identified 15 single nucleotide polymorphisms (SNPs) associated with non-Hodgkin lymphoma (NHL) and its subtypes. Because the incidence and subtype portion of NHL between the Chinese population and Caucasian populations are substantially different, we assessed the associatio...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgt082

    authors: Qiao Y,Zhou Y,Wu C,Zhai K,Han X,Chen J,Tian X,Chang J,Lu Z,Zhang B,Yu D,Yao J,Shi Y,Tan W,Lin D

    更新日期:2013-07-01 00:00:00

  • Ascorbic acid and beta-carotene as modulators of oxidative damage.

    abstract::Naturally occurring antioxidants are extensively studied for their capacity to protect organisms and cells from damage induced by oxygen reactive species. In fact, oxidative stress is considered a cause of aging, degenerative disease and cancer. We have focused our attention on two agents, ascorbic acid and beta-carot...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/18.1.223

    authors: Cozzi R,Ricordy R,Aglitti T,Gatta V,Perticone P,De Salvia R

    更新日期:1997-01-01 00:00:00

  • Carcinogenicity of nitropyrenes in the newborn female rat.

    abstract::The carcinogenicities of 1-nitropyrene (1-NP), 4-nitropyrene (4-NP), 1,3-dinitropyrene (1,3-DNP), 1,6-dinitropyrene (1,6-DNP), 1,8-dinitropyrene (1,8-DNP), 3-hydroxy-1-nitropyrene (3-OH-1-NP) and a mixture of 6- and 8-hydroxy-1-nitropyrene (6/8-OH-1-NP) were investigated in newborn female rats. Newborn female CD rats ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/16.12.3027

    authors: Imaida K,Lee MS,Land SJ,Wang CY,King CM

    更新日期:1995-12-01 00:00:00

  • Induction and time course of DNA single-strand breaks in lymphocytes from patients treated with dacarbazine.

    abstract::Dacarbazine (DTIC) is an antitumor agent, used for the treatment of metastatic melanoma. It is metabolized to an alkylating agent which reacts with DNA. A fast and simple method was developed in order to measure drug-induced DNA damage in lymphocytes isolated from frozen blood samples of treated patients. The level of...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/12.6.1153

    authors: Walles SA,Ringborg U

    更新日期:1991-06-01 00:00:00

  • Transfer and expression of human O6-methylguanine-DNA methyltransferase cDNA confers resistance of Mer- HeLa MR cells to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosoure a.

    abstract::Previous studies have demonstrated that O6-methylguanine-DNA methyltransferase (MGMT) is a major contributor to tumor cellular resistance toward chloroethylnitrosoureas. To further clarify the effect of MGMT gene expression on cellular chemosensitivity to 1-(4-amino-2-methyl-5-pyrimidinyl)-3-(2-chloroethyl)-3-nitrosou...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/16.9.2271

    authors: Yang J,Chen JM,Zhang YP

    更新日期:1995-09-01 00:00:00

  • Black raspberries inhibit N-nitrosomethylbenzylamine (NMBA)-induced angiogenesis in rat esophagus parallel to the suppression of COX-2 and iNOS.

    abstract::Angiogenesis, the formation of new blood vessels, is critical to tumor growth and metastasis. Vascular endothelial growth factor (VEGF), an important angiogenic activator, is essential for angiogenesis. Our laboratory has used a rodent model of human esophageal squamous cell carcinoma (ESCC) to identify putative chemo...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/bgl109

    authors: Chen T,Rose ME,Hwang H,Nines RG,Stoner GD

    更新日期:2006-11-01 00:00:00

  • GDP-fucose:GM1 alpha 1----2fucosyltransferase is activated in parenchymal cells of rat liver during early stages of N-2-acetylaminofluorene induced hepatocarcinogenesis.

    abstract::Gangliosides from liver parenchymal and non-parenchymal cells were isolated from Fischer 344 rats that had been fed normal diet or a diet supplemented with 0.03% N-2-acetylaminofluorene (AAF) for 4 weeks. Gangliosides from liver cell fractions were characterized by an induction of both II3NeuAcIV3 alpha GalIV2FucGg4 a...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/11.1.89

    authors: Holmes EH

    更新日期:1990-01-01 00:00:00

  • Studies on the antimutagenic activity of ascorbic acid in vitro and in vivo.

    abstract::The possibility that ascorbic acid, as a nucleophile, may inhibit mutagenicity induced by electrophilic metabolites of N-nitroso compounds was examined. In vitro data are presented to show that ascorbic acid does not decrease the mutagenicity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in a modified Ames bacterial ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/6.11.1593

    authors: Norkus EP,Kuenzig WA

    更新日期:1985-11-01 00:00:00

  • Morphologic transformation of the C3H 10T1/2 cell line is accompanied by altered expression of the p53 tumor suppressor gene.

    abstract::Wildtype 10T1/2 cells and 42 clonally derived morphologically transformed 10T1/2 cell lines were evaluated for expression of p53 mRNA and protein. Wildtype 10T1/2 cells expressed detectable levels of p53 mRNA and multiple immunologically distinct forms of the p53 protein, including both PAb240- and PAb246-reactive con...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/15.2.145

    authors: Coleman WB,Grisham JW,Smith GJ

    更新日期:1994-02-01 00:00:00

  • 32P-postlabeling analysis of adducts formed from 1-phenylazo-2-hydroxynaphthalene (Sudan I, Solvent Yellow 14) with DNA and homopolydeoxyribonucleotides.

    abstract::A 32P-postlabeling assay was employed for detection and quantitation of DNA adducts formed with carcinogenic 1-phenylazo-2-hydroxynaphthalene (Sudan I, Solvent Yellow 14) activated by a peroxidase system. Enrichment of adducts by digestion with nuclease P1 or by extraction into n-butanol prior to 32P-labeling was used...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/13.7.1221

    authors: Stiborová M,Frei E,Schmeiser HH,Wiessler M

    更新日期:1992-07-01 00:00:00

  • Expression of the glutathione S-transferase placental form in human lung carcinomas.

    abstract::Expression of glutathione S-transferase placental form (GST-pi) in human lung carcinoma tissue taken at autopsy or biopsy was investigated immunohistochemically. All of 34 cases of squamous cell carcinomas, including poorly, moderately and well-differentiated examples were shown to stain positively for GST-pi. Poorly ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/9.12.2325

    authors: Eimoto H,Tsutsumi M,Nakajima A,Yamamoto K,Takashima Y,Maruyama H,Konishi Y

    更新日期:1988-12-01 00:00:00

  • Striatal dopamine-stimulated adenylate cyclase activity reflects susceptibility of rats to 7,12-dimethylbenz[a]anthracene-induced mammary tumor development.

    abstract::The relationship between striatal dopamine-stimulated adenylate cyclase (DAC) and 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors was studied. An inverse correlation between activity of this enzyme and the number and growth of tumors was observed in several strains and substrains of rats. Chronic, but not...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/5.7.971

    authors: Goldman PR,Vogel WH

    更新日期:1984-07-01 00:00:00

  • The metabolism of N-nitrosobis(2-oxopropyl)amine by microsomes and hepatocytes from Fischer 344 rats.

    abstract::The metabolism of N-nitrosobis(2-oxopropyl)amine (BOP) was examined in microsomes from uninduced F-344 rats. Even when the conditions were varied, no metabolism of this compound was detected. On the other hand, freshly isolated hepatocytes from F-344 rats metabolized BOP efficiently to CO2. The kinetics of conversion ...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/8.8.1095

    authors: Farrelly JG,Saavedra JE,Kupper RJ,Stewart ML

    更新日期:1987-08-01 00:00:00

  • Tumorigenicity and metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol enantiomers and metabolites in the A/J mouse.

    abstract::4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a major metabolite of the tobacco-specific pulmonary carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), has a chiral center but the tumorigenicity of the NNAL enantiomers has not been previously examined. In this study, we assessed the relative tumori...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/20.8.1577

    authors: Upadhyaya P,Kenney PM,Hochalter JB,Wang M,Hecht SS

    更新日期:1999-08-01 00:00:00

  • Identification and mutagenicity of metabolites of aristolochic acid formed by rat liver.

    abstract::The rat liver 9000 g supernatant mediated metabolism of the carcinogenic aristolochic acid, which consists of aristolochic acid I (AAI) and aristolochic acid II (AAII), was investigated. Under anaerobic conditions the major metabolites were the corresponding aristolactams for both AAI and AAII. In contrast under aerob...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/7.1.59

    authors: Schmeiser HH,Pool BL,Wiessler M

    更新日期:1986-01-01 00:00:00

  • The role of O6-alkylguanine-DNA alkyltransferase in protecting Rat4 cells against the mutagenic effects of O6-substituted guanine residues incorporated in codon 12 of the H-ras gene.

    abstract::The role of rat O6-alkylguanine-DNA alkyltransferase (AGT) in modulating mutagenesis by O6-substituted guanines in the rat H-ras gene was examined. Rat4 cells were transfected with vectors carrying O6-methyl-, O6-ethyl- or O6-benzylguanine residues in place of the normal guanines at either the first, second, or both t...

    journal_title:Carcinogenesis

    pub_type: 杂志文章

    doi:10.1093/carcin/14.4.593

    authors: Bishop RE,Dunn LL,Pauly GT,Dolan ME,Moschel RC

    更新日期:1993-04-01 00:00:00