Human lung adenocarcinoma, the most prevalent form of lung cancer, is characterized by many molecular abnormalities. K-ras mutations are associated with the initiation of lung adenocarcinomas, but K-ras-independent mechanisms may also initiate lung tumors. Here, we find that the runt-related transcription factor Runx3 is essential for normal murine lung development and is a tumor suppressor that prevents lung adenocarcinoma. Runx3À/À mice, which die soon after birth, exhibit alveolar hyperplasia. Importantly, Runx3À/À bronchioli exhibit impaired differentiation, as evidenced by the accumulation of epithelial cells containing specific markers for both alveolar (that is SP-B) and bronchiolar (that is CC10) lineages. Runx3À/À epithelial cells also express Bmi1, which supports self-renewal of stem cells. Lung adenomas spontaneously develop in aging Runx3 þ /À mice (B18 months after birth) and invariably exhibit reduced levels of Runx3. As K-ras mutations are very rare in these adenomas, Runx3 þ /À mice provide an animal model for lung tumorigenesis that recapitulates the preneoplastic stage of human lung adenocarcinoma development, which is independent of K-Ras mutation. We conclude that Runx3 is essential for lung epithelial cell differentiation, and that downregulation of Runx3 is causally linked to the preneoplastic stage of lung adenocarcinoma.

5-(Hydroxymethyl)furfural (HMF), one of the major intermediate products in the Maillard reaction, is present in a wide variety of foods. This aldehyde is formed as a decomposition product of glucose and fructose in foodstuffs subject to cooking or heat sterilization. It has been found to possess mutagenic and DNA strand-breaking activity. However, the mechanisms by which HMF exerts its genotoxicity remain unclear. The present study was undertaken to determine if HMF could be metabolically activated via esterification of the allylic hydroxyl group. In support of this concept, the chemically synthesized sulfuric acid ester,5-[(sulfooxy)-methyl]furfural (SMF), exhibited direct mutagenicity at both thymidine kinase and hypoxanthine-guanine phosphoribosyltransferase loci in human lymphoblasts. This reactive ester also induced 8-azaguanine-resistant mutants in Salmonella typhimurium TM677 in a dose-dependent manner. The intrinsic mutagenicity of SMF was enhanced by addition of extra chloride ion to the assay medium. The model allylic derivative, 5-(chloromethyl)furfural, was also mutagenic and cytotoxic in bacteria, but much more active than the sulfuric acid ester in this regard. In contrast to (sulfooxy)methyl and chloromethyl derivatives of HMF,2-[(sulfooxy)-methyl]- and 2-(chloromethyl)furans which lack the aldehyde functionality did not exhibit significant mutagenicity. Rodent hepatic cytosols contained sulfotransferase activity responsible for the formation of the reactive allylic sulfuric acid ester metabolite from HMF.

Two known diarylheptanoids, oregonin (1), (5S)-1,7-bis-(3,4-dihydroxyphenyl)-heptane-3-one-5-O-beta-D-xylopyranosi de and hirsutanonol (2), (5S)-1,7-bis-(3,4-dihydroxyphenyl)-5-hydroxyheptane-3-one isolated from the bark of Alnus hirsuta var. sibirica, showed significant inhibitory effects on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cyclooxygenase-2 (COX-2) expression in immortalized human breast epithelial MCF10A cells.

Our previous studies on 7-hydroxymethyl-12-methylbenz[a]anthracene and 6-hydroxymethylbenzo[a]pyrene showed that cytosolic sulfotransferase activity plays a major role in the formation of hepatic benzylic DNA and RNA adducts by these carcinogens in rats. In the present study, we found similar sulfotransferase activity in rat liver cytosol which activates 9-hydroxymethyl-10-methylanthracene (HMA) and 1-hydroxymethylpyrene (HMP) to electrophilic sulfuric acid ester metabolites. Thus, incubation of these nonbay region hydrocarbons with calf thymus DNA in the presence of liver cytosol fortified with the sulfo-group donor, 3'-phosphoadenosine-5'-phosphosulfate (PAPS) produced benzylic DNA adducts that were chromatographically identical to those obtained by the reactions of the corresponding sulfuric acid esters with deoxyguanosine and deoxyadenosine. These adducts were also produced in the livers of infant rats injected i.p. with 0.25 mumol/g body wt of HMA or HMP. Administration of comparable doses of 9-sulfooxymethyl-10-methylanthracene (SMA) and 1-sulfooxymethylpyrene (SMP) resulted in much higher levels of hepatic benzylic DNA adducts than did the parent hydroxymethyl hydrocarbons. Both HMA and HMP induced His+ revertants in Salmonella typhimurium TA98 when preincubated with these bacteria in the presence of rat liver cytosol and PAPS. This sulfotransferase-mediated mutagenicity of HMA and HMP was reduced by dehydroepiandrosterone, an inhibitor of hepatic sulfotransferase activity for these hydrocarbons. SMA and SMP were directly mutagenic and their intrinsic bacterial mutagenicity was inhibited by glutathione (GSH) and GSH-S-transferase activity. Chloride ion at physiological concentrations enhanced the bacterial mutagenicity of SMA through the formation of 9-chloromethyl-10-methylanthracene as previously observed for SMP by Henschler et al. In contrast to the higher mutagenicity of 1-chloromethylpyrene (CMP) than SMP in bacteria, CMP formed smaller amounts of hepatic benzylic DNA adducts in rats than the sulfuric acid ester. SMA and SMP were weak skin tumor initiators in the mouse, but they were more active than HMA and HMP in this regard.

Although debates still exist whether Helicobacter pylori infection is really class I carcinogen or not, H. pylori has been known to provoke precancerous lesions like gastric adenoma and chronic atrophic gastritis with intestinal metaplasia as well as gastric cancer. Chronic persistent, uncontrolled gastric inflammations are possible basis for ensuing gastric carcinogenesis and H. pylori infection increased COX-2 expressions, which might be the one of the mechanisms leading to gastric cancer. To know the implication of long-term treatment of antiinflammatory drugs, rebamipide or nimesulide, on H. pylori-associated gastric carcinogenesis, we infected C57BL/6 mice with H. pylori, especially after MNU administration to promote carcinogenesis and the effects of the long-term administration of rebamipide or nimesulide were evaluated. C57BL/6 mice were sacrificed 50 weeks after H. pylori infection. Colonization rates of H. pylori, degree of gastric inflammation and other pathological changes including atrophic gastritis and metaplasia, serum levels and mRNA transcripts of various mouse cytokines and chemokines, and NF-kappaB binding activities, and finally the presence of gastric adenocarcinoma were compared between H. pylori infected group (HP), and H. pylori infected group administered with long-term rebamipide containing pellet diets (HPR) or nimesulide mixed pellets (HPN). Gastric mucosal expressions of ICAM-1, HCAM, MMP, and transcriptional regulations of NF-kappaB binding were all significantly decreased in HPR group than in HP group. Multi-probe RNase protection assay showed the significantly decreased mRNA levels of apoptosis related genes and various cytokines genes like IFN-gamma, RANTES, TNF-alpha, TNFR p75, IL-1beta in HPR group. In the experiment designed to provoke gastric cancer through MNU treatment with H. pylori infection, the incidence of gastric carcinoma was not changed between HP and HPR group, but significantly decreased in HPN group, suggesting the chemoprevention of H. pylori-associated gastric carcinogenesis by COX-2 inhibition. Long-term administration of antiinflammatory drugs should be considered in the treatment of H. pylori since they showed the molecular and biologic advantages with possible chemopreventive effect against H. pylori-associated gastric carcinogenesis. If the final concrete proof showing the causal relationship between H. pylori infection and gastric carcinogenesis could be obtained, that will shed new light on chemoprevention of gastric cancer, that is, that gastric cancer could be prevented through either the eradication of H. pylori or lessening the inflammation provoked by H. pylori infection in high risk group.