title: 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.
authors.affiliation: Institute of Toxicology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Bopp
authors.affiliation: Institute of Toxicology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Wartlick
authors.affiliation: Institute of Toxicology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Henninger
authors.affiliation: Institute of Pharmacology and Toxicology, University Tübingen, Wilhelmstrasse 76, D-72074 Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
authors.affiliation: Institute of Toxicology, University Medical Center Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany and.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
authors.affiliation: Institute of Toxicology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany, fritz@uni-duesseldorf.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fritz
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D002453:Cell Cycle / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004052:Diethylnitrosamine / Q000633:toxicity*; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D005092:Exonucleases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D002273:Carcinogens; D004052:Diethylnitrosamine; D004798:Enzymes; D005092:Exonucleases; D006657:Histones; D009479:Neuropeptides; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins; C484602:Rac1 protein, mouse; C559924:Rad1 protein, mouse; C475961:gamma-H2AX protein, mouse