-
[show abstract]
[hide abstract]
ABSTRACT: The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. PPARγ ligands can inhibit cell growth and increase apoptosis of cancer cell lines, suggesting a potential role for PPARγ as a tumor suppressor. Whereas the related studies between PPARγ and cancer cell invasion are still poor. Our previous study indicates that β-estradiol (E2) suppresses hepatocellular carcinoma (HCC) cell invasion. We report here that E2 can activate PPARγ of HCC cells, and activated PPARγ suppresses cell invasion by up-regulating the expression level of plasminogen activator inhibitor-1 (PAI-1). We found that PPARγ plays an important role in the E2-induced HCC cell invasion process. Using PPARγ agonist GW1929, a reduced invasion effect was found in HCC cell lines, and this inhibition of cell invasion was dosage-dependent. However, cell invasion was restored by treatment with PPARγ antagonist GW9662. The activated PPARγ up-regulated the expression of cell migration-related protein PAI-1. Furthermore, knockdown of PPARγ in HCC cells decreased the level of PAI-1 and advanced cell invasion in response to GW1929. On the contrary, overexpression of PPARγ in HCC cells elevated the level of PAI-1 and inhibited cell invasion. These findings suggest that PPARγ activation inhibits HCC cell invasion via the up-regulation of PAI-1 and implicate that PPARγ is a target for the treatment and prevention of HCC cell invasion.
Cancer Science 03/2013; · 3.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The precise mechanisms underlying gender disparity in hepatocellular carcinoma (HCC) progression and prognosis are not understood. We demonstrate that oestrogen attenuates HCC progression in vitro and in vivo, and this may contribute to the gender differences in HCC behaviour. To investigate the role of oestrogen in HCC progression, we developed an orthotopic homograft tumour model by liver implantation of H22 cells. In combination with male castration, female ovariectomy, and oestrogen treatment, we tested the hypothesis that oestrogen contributes to gender disparity in this model. Pathological analyses were performed to examine the changes in biological behaviour of liver cancer cells, and two cell lines were used to investigate possible molecular mechanisms of the suppressive effect of oestrogen. Our data showed that oestrogen modulates HCC malignancy in vivo by reducing tumour cell invasion, arresting cell cycle progression, and promoting apoptosis, characterized by decreased expression of MMP-2, MMP-9, PCNA, cyclin A, cyclin D1, and Bcl-2, and increased expression in cleaved caspase 3. Through in vitro assays, we further confirmed the changes in expression levels of these related proteins, gained insights into the molecular cascades of oestrogen-induced HCC suppression, and indicated the oestrogen receptor α-mediated inhibition of NF-κB binding activity as a pivotal event in this process. This study represents a novel description of the mechanisms regarding the suppressive effects of oestrogen on HCC, adding a new understanding to the gender disparity in HCC progression. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology 02/2012; 228(2):216-29. · 6.32 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: From the view of membrane permeability transition (MPT) to study the mechanism of microcystin (MCs) inducing hepatocyte apoptosis in mice, and unclose the function of reactive oxygen species (ROS) in this process.
Use the mice as the model animals and randomly divide them into 4 groups. Group A were injected with physiological saline peritoneal in abdomen, while group B were injected with MC-LR 50 microg/kg bw in abdomen, group C were injected with the MPT inhibitor, Cyclosporin A (CsA) 100 mg/kg bw, in abdomen, and group D were injected with CsA 100 mg/kg bw in abdomen, and then after 1 hour, with MC-LR 50 microg/kg bw. Separate the mice serum, measure AST and ALT concentrations. Separate the mice livers and then perform the mice liver DNA segment detection, mitochondrion membrane potential level measurement, ROS level measurement and western blotting measurement at the expression level of Bcl-2.
In the group treated with 50 microg/kg bw MC-LR, in the serum, the AST and ALT levels rised. In the liver cells, there was significant DNA ladder, the the expression of Bcl-2 at the level of protein increased, mitochondrion membrane potential level of liver tissue decreased, and the ROS level in the tissue increased. In the group treated with 100 mg/kg bw CsA, every index of the mice has no significant change. While with the pre-treatment of 100 mg/kg bw CsA, and then with 50 microg/kg bw MC-LR in abdomen, the DNA ladder in the liver tissue can be removed, and the serum AST and ALT concentrations, the expression of liver Bcl-2 protein, the mitochondrion membrane potential level and ROS level were conversed to the levels of the control group.
In vivo the inhibition of transition channel of mitochondrion membrane can inhibit the hepatocyte apoptosis induced by MC-LR.
Wei sheng yan jiu = Journal of hygiene research 01/2011; 40(1):53-6.
-
[show abstract]
[hide abstract]
ABSTRACT: Mitochondrial apoptotic pathway is precisely controlled by BCL-2 family. Complex interactions of BCL-2 family proteins constitute a bistable switch of which detailed experimental and theoretical delineation remains elusive. In this paper, combined approaches were used to explore the bistability of Bax activation switch. We found that Bax activation is indeed in an 'all-or-none' manner. The 'variable-delay, snap-action' nature for Bax activation is further explored theoretically. We suggest that bistability is largely attributed to topological structure and shows considerable robustness. Therefore, our study characterizes dynamics and sensitivities in intrinsic apoptotic pathway.
FEBS letters 03/2010; 584(5):954-60. · 3.54 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Microcystin-LR (MC-LR) produced by cyanobacteria in diverse water systems is a potent specific hepatotoxin and has been documented to induce various liver diseases via oxidative stress. However, the underlying mechanisms are largely unknown. In the current study, we investigated the molecular events involved in the oxidative liver injury by MC-LR. Our results demonstrated that MC-LR induced liver injury in mice through a series of steps that began with the production of reactive oxygen species (ROS), which stimulated the sustained activation of JNK and its downstream targets, AP-1 and Bid. Furthermore, the mitochondrial proteomic analysis indicated that JNK activation affected some crucial enzymes of energy metabolism, led to mitochondria dysfunction, which contributed to hepatocyte apoptosis and oxidative liver injury by MC-LR. Our results reveal significant insights into the mechanisms of liver injury induced by microcystins, and serve as a framework for deciphering the role of JNK in oxidative stress-associated liver diseases.
Apoptosis 09/2008; 13(8):1031-42. · 4.07 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Microcystin-LR (MC-LR) produced by cyanobacteria in diverse water systems is a potent specific hepatotoxin and has been documented to induce hepatocyte apoptosis and liver injury; however, the mechanisms have not been fully elucidated. In the present study, we investigated whether MC-LR stimulated ROS generation in the liver of mice and the role of ROS in the pathogenesis of MC-LR-induced liver injury in vivo. MC-LR treatment (60 microg/kg of body weight) for 12h prompted large amount of ROS generation in mice liver, upregulated the expression of Bax and Bid, caused the mitochondrial membrane potential (MMP) loss and hepatocyte apoptosis as well as liver injury. While pretreatment with antioxidants, oral administration of vitamin C (250mg/kg of body weight, dissolved in double distill water) and vitamin E (200mg/kg of body weight, dissolved in corn oil) per day for 3 days continually, significantly reduced the generation of ROS and effectively inhibited the MC-LR-induced hepatocyte apoptosis and liver injury, suggesting that ROS played a critical role in MC-LR-induced hepatocyte apoptosis and liver injury. The protective effect of vitamin C and E also suggested the potential interest in the clinical treatment of MC-LR-induced liver injury and hepatotoxicity.
Toxicology 04/2007; 232(1-2):15-23. · 3.68 Impact Factor
