Apoptosis and proliferation in hepatocarcinogenesis related to cirrhosis

Park, Young Nyun; Chae, Boah; Kim, Young Bae; Park, Chan-Il; Theise, Neil D.

doi:10.1002/1097-0142(20011201)92:11<2733::aid-cncr10126>3.0.co;2-5

Cited by 55 publications

(31 citation statements)

References 66 publications

(56 reference statements)

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“…We found that TUNEL LI was significantly higher in HCC than in non-tumor tissue, a result that is in agreement with previous studies (recent last 2 years) (8)(9)(10). However, the ratio of TUNEL LI/PCNA LI that we observed in HCC was lower than that of non-tumor tissue.…”

Section: Discussionsupporting

confidence: 93%

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Cellular apoptosis susceptibility protein and proliferation in human hepatocellular carcinoma

Shiraki

Fujikawa²,

Sugimoto³

et al. 2006

Int J Mol Med

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Abstract. The cellular apoptosis susceptibility protein (CAS) is the human homologue of the product of the essential yeast chromosome segregation gene, CSE1, and has important roles in tumor necrosis factor (TNF)-induced apoptosis and cell proliferation. In this study, we used immunoblotting and immunohistochemistry to look at CAS expression in human hepatocellular carcinoma (HCC) cells. We also sudied the correlation between CAS expression and cell proliferation. To do this, we studied the expression of proliferating cell nuclear antigen (PCNA) by immunostaining and at apoptosis by in situ nick end-labeling (TUNEL), followed by calculation of the PCNA labeling index (PCNA LI) and TUNEL labeling index (TUNEL LI). CAS was constitutively expressed in human HCC cell lines and was primarily confined to the cytoplasm of the cells. PCNA LI and TUNEL LI were significantly higher in HCC than in non-tumor tissue (p<0.01); however, the ratio of TUNEL LI/PCNA LI in HCC was significantly lower than that of non-tumor tissue. Immunohistochemistry revealed that the staining intensity score of CAS in HCC was significantly higher than that of non-tumor tissue (p<0.05). These results indicate that there is an augmentation of pro-liferative activity and apoptosis in HCC tissue, as compared to non-tumor tissue. There was a significant positive correlation between CAS and PCNA LI (p<0.05). In addition, we observed an inverse relationship between CAS expression and TUNEL LI, although the correlation did not reach statistical significance. These results suggest that CAS is expressed at higher levels in human HCC tissue than in non-tumor tissue. CAS may be associated with cell proliferation rather than apoptosis, and further, CAS might play an important role in the development of human HCCs.

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Section: Discussionsupporting

confidence: 93%

“…Cell proliferation and inhibition of apoptosis are thought to be important to the development of cancer (8)(9)(10). However, how regulation of the CAS gene may relate to cell proliferation or apoptosis in HCCs is not well understood.…”

Section: Introductionmentioning

confidence: 99%

Cellular apoptosis susceptibility protein and proliferation in human hepatocellular carcinoma

Shiraki

Fujikawa²,

Sugimoto³

et al. 2006

Int J Mol Med

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“…The deregulation of apoptosis and the accelerated proliferate activity of hepatocytes have been reported as significant steps for hepatocarcinogenesis [20,21]. During hepatocarcinogenesis, some of the genetically altered hepatocytes progress to apoptosis and some escape from the apoptosis and undergo carcinogenesis [21].…”

Section: Introductionmentioning

confidence: 99%

Pleiotrophin inhibits transforming growth factor β1‐induced apoptosis in hepatoma cell lines

Park

Jeong

Tateno³

et al. 2008

Molecular Carcinogenesis

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Pleiotrophin (PTN) is a hepatocyte growth factor and considered to play roles in liver fibrogenesis and hepatocarcinogenesis. In this study we examined the mechanism of the action of PTN in these pathological processes. First, we confirmed that hepatic stellate cells (HSCs) and Kupffer cells, and also later hepatocytes in hyperplastic nodules increased PTN mRNA expressions during carbon tetrachloride-induced liver fibrosis. Then, the relationship between PTN and transforming growth factor b1 (TGFb1), a known potent pro-fibrogenetic cytokine, in carcinogenesis was investigated using hepatoma cell lines. Huh-7 human hepatoma cells weakly expressed PTN, but HepG2 human hepatoma cells and FaO rat hepatoma cells did not. Recombinant (r) TGFb1 induced the cultured Huh-7 cells to undergo apoptosis, which was inhibited by rPTN. Huh-7 cells became resistant to TGFb1-, but not mitomycin C-induced apoptosis when transfected with PTN gene, indicating the specificity of the PTN anti-apoptotic activity. Poly ADP ribose polymerase, procaspase-8 and procaspase-3 were not cleaved in the TGFb1-reluctant cells. The TGFb1-induced caspase-3 activation was also suppressed in Huh-7 and FaO cells both transduced with PTN gene-bearing adenoviruses. In summary, PTN was expressed in HSCs, Kupffer cells, and hepatocytes in fibrotic liver. We propose that PTN specifically antagonizes the TGFb1 activity during liver fibrosis. ß

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“…16 -18 Deregulation of apoptosis in hepatic cells and accelerated proliferative activity in hepatic cells have been reported as significant factors with respect to hepatocarcinogenesis or tumor progression in HCC. 19 In fact, it is known that HCC is resistant to Fas-mediated apoptosis, and a common defect in the expression of Fas, up-regulation of Fas-associated phosphatases, and down-regulation of downstream molecules, such as Fas-associated death domain and caspase-8, have been noted in HCC. 20 Apoptosis is essential for normal development and tissue homeostasis.…”

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confidence: 99%

Midkine protects hepatocellular carcinoma cells against TRAIL‐mediated apoptosis through down‐regulation of caspase‐3 activity

Ohuchida

Okamoto

Akahane

et al. 2004

Cancer

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BACKGROUNDIt is believed that midkine (MK), a heparin‐binding growth factor, plays an important role in carcinogenesis. However, the biologic mechanism of MK in hepatocellular carcinoma has not been clarified to date. The objective of the current study was to investigate the antiapoptotic role of MK in a human hepatoma cell line.METHODSThe human hepatoma cell line HepG2 was used to study the antiapoptotic effect of MK. Tumor necrosis factor–related apoptosis‐inducing ligand (TRAIL)/actinomycin D (ActD)–induced apoptosis was detected using a 2‐(2‐methoxy‐4‐nitrophenyl)‐3‐(4‐nitrophenyl)‐5‐(2,4‐disulphophenyl)‐2H‐tetrazolium monosodium salt (WST‐8) assay, a caspase‐3 activity assay, a caspase‐8 activity assay, and flow cytometric analysis.RESULTSTRAIL had a potent, dose‐dependent inductive effect on cell death in HepG2 cells, for which viable cell counts decreased to 6.3% of the control count at a TRAIL concentration of 100 ng/mL in the presence of 500 ng/mL ActD. Flow cytometry was used to demonstrate that apoptosis induced by TRAIL/ActD was in fact the cause of cell death. According to the WST‐8 assay, MK pretreatment resulted in the suppression of TRAIL/ActD‐mediated apoptosis in HepG2 cells, although cell viability did not increase when HepG2 cells were treated with MK alone. Caspase‐3 activity was down‐regulated when MK was added, but caspase‐8 activity was high in both the absence and presence of MK.CONCLUSIONSThe results of the current study indicate that MK acts as an antiapoptotic factor in HepG2 cells through the down‐regulation of caspase‐3 activity. Cancer 2004. © 2004 American Cancer Society.

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Apoptosis and proliferation in hepatocarcinogenesis related to cirrhosis

Cited by 55 publications

References 66 publications

Cellular apoptosis susceptibility protein and proliferation in human hepatocellular carcinoma

Cellular apoptosis susceptibility protein and proliferation in human hepatocellular carcinoma

Pleiotrophin inhibits transforming growth factor β1‐induced apoptosis in hepatoma cell lines

Midkine protects hepatocellular carcinoma cells against TRAIL‐mediated apoptosis through down‐regulation of caspase‐3 activity

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