beta-ionone and Precancerous-Conditions

MicroRNAs (miRNAs) are post-transcriptional gene expression regulators which expression is frequently altered in hepatocellular carcinoma (HCC). β-ionone (βI) is noted for its ability to inhibit persistent preneoplastic lesions (pPNLs) in liver rats. We evaluated the expression of miRNAs involved in carcinogenesis and possible targets modulated by βI, in pPNLs and surrounding of microdissected tissues. Rats subjected to resistant hepatocyte model were treated during promotion stage with βI (16 mg/100 g body weight) or corn oil (CO; 0.25 mL/100 g body weight; controls). Five animals receive no treatment (NT). In CO group, 38 and 29 miRNAs showed reduced expression relative to NT (P < 0.05) in pPNLs and surrounding, respectively. No miRNAs showed increased expression in surrounding of the CO compared to NT group; however, 30 miRNAs showed increased expression (P ≤ 0.05) in pPNLs of the CO group. There was no difference between βI and CO groups (P > 0.05) in the expression of miRNAs in surrounding. In pPNLs βI increased expression of miR-122 and miR-34a (P ≤ 0.05) and reduced of Igf2 (P ≤ 0.05), target of the latter, compared to CO. Additionally, βI decreased the expression of miR-181c and its target Gdf2 (P ≤ 0.05). βI reduced the expression of miR-181b and miR-708 (P ≤ 0.05) and increased the expression of their respective target mRNAs Timp3 and Mtss1 (P ≤ 0.05), relative to CO group. Modulation of miRNAs target genes by βI was confirmed in vitro. βI is a promising chemopreventive agent in the initial stages of hepatocarcinogenesis, as it modulates the expression of the miRNAs and target genes that can alter the metastatic phenotype of HCC. © 2016 Wiley Periodicals, Inc.

Topics: Animals; Anticarcinogenic Agents; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Liver; Liver Neoplasms; Male; MicroRNAs; Norisoprenoids; Precancerous Conditions; Rats; Rats, Wistar

Chemopreventive activities of the dietary isoprenoids β-ionone (βI) and geraniol (GOH) were evaluated during the promotion phase of hepatocarcinogenesis. Over 5 consecutive weeks, rats received daily 16 mg/100 g body weight (b.w.) of βI (βI group), 25 mg/100 g b.w. of GOH (GOH group), or only corn oil (CO group, controls). Compared to the CO group, the following was observed: only the βI group showed a decrease in the mean number of visible hepatocyte nodules (P<.05); βI and GOH groups had reduced mean number of persistent preneoplastic lesions (pPNLs) (P<.05), but no differences regarding number of remodeling PNL (rPNLs) were observed; only the βI group exhibited smaller rPNL size and percentage of liver sections occupied by pPNLs (P<.05), whereas the GOH group displayed a smaller percentage of liver sections occupied by rPNLs (P<.05); a trend was observed in the βI group, which showed reduced cell proliferation of pPNLs (P<.10), and the GOH group had increased apoptosis in pPNLs and rPNLs (P<.05); only the βI group displayed reduced total plasma cholesterol concentrations (P<.05) and increased hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase mRNA levels (P<.05); only the GOH group had lower hepatic membrane RhoA protein levels (P<.05); both the βI- and GOH-treated groups had higher hepatic concentrations of βI and GOH, respectively (P<.05). Given these data, βI and GOH show promising chemopreventive effects during promotion of hepatocarcinogenesis by acting through distinct mechanism of actions: βI may inhibit cell proliferation and modulate HMGCoA reductase, and GOH can induce apoptosis and inhibit RhoA activation.

Topics: Acyclic Monoterpenes; Animals; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Chemoprevention; Cholesterol; Hydroxymethylglutaryl CoA Reductases; Liver; Liver Neoplasms; Male; Norisoprenoids; Precancerous Conditions; Rats; Rats, Wistar; rhoA GTP-Binding Protein; Terpenes

Chemopreventive activities of the isoprenoids geranylgeraniol (GGO) and beta-ionone (BI) were evaluated during initial phases of hepatocarcinogenesis. Rats received 8 or 16 mg/100 g body wt GGO (GGO8 and GGO16 groups) or BI (BI8 and BI16 groups), or only corn oil (CO group, controls) daily for 7 weeks. Incidence (%) and the mean number of visible hepatocyte nodules/animal were inhibited in the GGO8 (64% and 21 +/- 40), GGO16 (33% and 3 +/- 5), BI8 (50% and 13 +/- 34) and BI16 (42% and 9 +/- 19) groups compared with the CO group (100% and 34 +/- 51) (P < 0.05, except for the GGO8 group). Number/cm(2) liver section, mean area (mm(2)) and % liver section area occupied by persistent hepatic placental glutathione S-transferase positive preneoplastic lesions (PNL) were reduced in the GGO8 (11 +/- 9; 0.26 +/- 0.35; 2.7 +/- 3.0), GGO16 (6 +/- 6; 0.18 +/- 0.16; 0.9 +/- 0.9), BI8 (9 +/- 5; 0.13 +/- 0.20; 1.1 +/- 1.2) and BI16 (8 +/- 6; 0.08 +/- 0.09; 0.6 +/- 0.4) groups compared with the CO group (26 +/- 18; 0.29 +/- 0.34; 7.0 +/- 5.5) (P < 0.05). GGO16 and BI16 groups showed smaller visible hepatocyte nodules, reduced PNL cell proliferation and total plasma cholesterol levels compared with the CO group (P < 0.05), but did not show any differences (P > 0.05) in PNL apoptosis. DNA damage expressed as comet length (microm) was reduced in the GGO8 (96.7 +/- 1.5), GGO16 (94.2 +/- 1.5), BI8 (97.1 +/- 1.1) and BI16 (95.1 +/- 1.5) groups compared with the CO group (102.1 +/- 1.7) (P < 0.05). In comparison with normal animals, the CO group animals showed increased (P < 0.05) nuclear levels of nuclear factor kappa B (NF-kappaB) p65 subunit in hepatic cells, which were decreased (P < 0.05) in the GGO16 group animals. Anticarcinogenic actions of these isoprenoids seem to follow a dose-response relationship. Results indicate that GGO and BI could be represented as promising chemopreventive agents against hepatocarcinogenesis. Inhibition of cell proliferation and DNA damage seems to be important for the anticarcinogenic actions of isoprenoids, while the inhibition of NF-kappaB activation seems to be specifically related to GGO actions.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Cell Proliferation; Cholesterol; Corn Oil; Diterpenes; DNA Damage; Enzyme Activation; Hepatocytes; Liver Neoplasms, Experimental; Male; NF-kappa B; Norisoprenoids; Precancerous Conditions; Rats; Rats, Wistar; Transcription Factor RelA