Impact of PTEN expression on the outcome of hepatitis C virus‐positive cirrhotic hepatocellular carcinoma patients: Possible relationship with COX II and inducible nitric oxide synthase

Rahman, Mohammad Atiqur; Kyriazanos, Ioannis; Ono, Takashi; Yamanoi, Akira; Kohno, Hitoshi; Tsuchiya, Mikako; Nagasue, Naofumi

doi:10.1002/ijc.10458

Cited by 56 publications

(36 citation statements)

References 28 publications

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“…Consistent with previous studies, loss of PTEN was associated with larger tumor size, providing evidence for Akt-mTORC1 activation in more advanced HCC lesions. An evaluation of IHS for PTEN in 46 HCC specimens from patients with HCV found low levels of expression in 63% of cases that was associated with reduced survival after surgical resection [30]. Akt activity, which is down regulated by PTEN, was found to be increased by western blot analysis in patients with low levels of PTEN expression.…”

Section: Discussionmentioning

confidence: 97%

Immunohistochemical Expression of Components of the Akt-mTORC1 Pathway is Associated with Hepatocellular Carcinoma in Patients with Chronic Liver Disease

et al. 2007

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Section: Discussionmentioning

confidence: 97%

Immunohistochemical Expression of Components of the Akt-mTORC1 Pathway is Associated with Hepatocellular Carcinoma in Patients with Chronic Liver Disease

et al. 2007

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“…There is growing evidence of PTEN/PI3K/Akt pathway in hepatocarcinogenesis [27,32,[47][48][49] . PTEN is a tumor suppressor gene and the deletion or inactivation of this gene has been described in a variety of cancer cell lines [30,33,53] .…”

Section: Discussionmentioning

confidence: 99%

“…PTEN is an upstream negative regulator of Akt. It was reported that altered PTEN expression or activity is associated with the pathogenesis of HCC [47][48][49] . In the present study, we found that silibinin at IC50 dose did not significantly change PTEN expression (data not shown), but significantly increased PTEN activity ( Figure 6E).…”

Section: Effects Of Silibinin On Pten/pi3k/akt Pathwaymentioning

confidence: 99%

Effects and mechanisms of silibinin on human hepatoma cell lines

Lah

Cui²,

Hu³

2007

WJG

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AIM:To investigate in vitro effects and mechanisms of silibinin on hepatocellular carcinoma (HCC) cell growth. METHODS:Human HCC cell lines were treated with different doses of silibinin. The effects of silibinin on HCC cell growth and proliferation, apoptosis, cell cycle progression, histone acetylation, and other related signal transductions were systematically examined. RESULTS:We demonstrated that silibinin significantly reduced the growth of HuH7, HepG2, Hep3B, and PLC/PRF/5 human hepatoma cells. Silibinin-reduced HuH7 cell growth was associated with significantly upregulated p21/CDK4 and p27/CDK4 complexes, downregulated Rb-phosphorylation and E2F1/DP1 complex. Silibinin promoted apoptosis of HuH7 cells that was associated with down-regulated survivin and upregulated activated caspase-3 and -9. Silibinin's antiangiogenic effects were indicated by down-regulated metalloproteinase-2 (MMP2) and CD34. We found that silibinin-reduced growth of HuH7 cells was associated with increased activity of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and decreased p-Akt production, indicating the role of PTEN/ PI3K/Akt pathway in silibinin-mediated anti-HCC effects. We also demonstrated that silibinin increased acetylation of histone H3 and H4 (AC-H3 and AC-H4), indicating a possible role of altered histone acetylation in silibininreduced HCC cell proliferation. CONCLUSION:Our results defined silibinin's in vitro anti-HCC effects and possible mechanisms, and provided a rationale to further test silibinin for HCC chemoprevention.

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“…For example, the immune system recognizes and eliminates tumor cells because of their expression of tumor-associated antigens (e.g. HER-2/neu in breast carcinomas)(1) but chronic inflammation resulting in enhanced epithelial cell turn over may be a major contributor to carcinogenesis.(2) Furthermore, neoplastic transformation and progression is associated with the release of highly reactive oxygen and nitrogen species (RONS) from inflammatory cells.(3) Hydrogen peroxide, nitric oxide (NO) or other RONS can damage DNA via several mechanisms, and NO is recognized to stimulate proinflammatory cytokines as well as cyclooxygense-2 (COX-2) activity, leading to tumor growth via enhanced prostaglandin production and inactivation of p53-mediated caspase.(4) Increased expression of inducible nitric oxide synthase (iNOS) or COX-2 in tumor epithelial cells as well as stromal inflammatory cells has been demonstrated in human gastric, (5) colon, (6,7) breast (8) and hepatic (9) tumors, and their contribution to tumor development and progression is now generally accepted. Overexpression of iNOS and COX-2 has also been reported in azoxymethane-induced colon, (10) 7,12-dimethylbenz(a)anthracene-induced mammary,…”

mentioning

confidence: 99%

“…(4) Increased expression of inducible nitric oxide synthase (iNOS) or COX-2 in tumor epithelial cells as well as stromal inflammatory cells has been demonstrated in human gastric, (5) colon, (6,7) breast (8) and hepatic (9) tumors, and their contribution to tumor development and progression is now generally accepted. Overexpression of iNOS and COX-2 has also been reported in azoxymethane-induced colon, (10) 7,12-dimethylbenz(a)anthracene-induced mammary,…”

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confidence: 99%

Depression of T cell‐mediated immunity reduces sulfadimethoxine‐induced capsular inflammation and inhibits associated development of invasive thyroid follicular cell carcinomas in rats

et al. 2007

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We previously demonstrated that thyroid capsular inflammation induced by continuous treatment with the antithyroidal agent sulfadimethoxine is associated with development of invasive follicular cell carcinomas in rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). The inflammatory changes are characterized by large numbers of macrophages and lymphocytes as well as fibroblasts and we hypothesized that it might be enhanced by interplay between macrophages and T cells. To clarify this hypothesis, a comparative study was conducted between athymic nude (rnu/rnu) rats and euthymic (rnu/+) littermates initiated with DHPN (2800 mg/kg, s.c.) followed by sulfadimethoxine treatment in drinking water (0.1%) for 10 weeks. In rnu/+rats, marked capsular thickening with inflammation was induced along with invasive follicular cell carcinomas (2.8 ± ± ± ± 1.3/rat). In rnu/rnu rats, limited fibrous capsular thickening was noted with or without minimal inflammatory change, and the multiplicity of invasive carcinomas was significantly lower (1.1 ± ± ± ± 1.0/ rat, P < 0. I t is generally accepted that inflammation is an immune reaction not only to exogenous but also to mutated or overexpressed endogenous proteins. It has both advantages and disadvantages for humans and animals. For example, the immune system recognizes and eliminates tumor cells because of their expression of tumor-associated antigens (e.g. HER-2/neu in breast carcinomas)(1) but chronic inflammation resulting in enhanced epithelial cell turn over may be a major contributor to carcinogenesis.(2) Furthermore, neoplastic transformation and progression is associated with the release of highly reactive oxygen and nitrogen species (RONS) from inflammatory cells.(3) Hydrogen peroxide, nitric oxide (NO) or other RONS can damage DNA via several mechanisms, and NO is recognized to stimulate proinflammatory cytokines as well as cyclooxygense-2 (COX-2) activity, leading to tumor growth via enhanced prostaglandin production and inactivation of p53-mediated caspase.(4) Increased expression of inducible nitric oxide synthase (iNOS) or COX-2 in tumor epithelial cells as well as stromal inflammatory cells has been demonstrated in human gastric, (5) colon, (6,7) breast (8) and hepatic (9) tumors, and their contribution to tumor development and progression is now generally accepted. Overexpression of iNOS and COX-2 has also been reported in azoxymethane-induced colon, (10) 7,12-dimethylbenz(a)anthracene-induced mammary,choline-deficient, l-amino acid-defined diet-caused hepatocellular,and indium-phosphate-induced lung (13) carcinogenesis in rats. Monocytes, macrophages and neutrophils produce iNOS in inflammatory states (14) in response to cytokines such as interferon (IFN)-γ.(15) Th1 and CD8 + T cells are major sources of IFN-γ during immunoresponses, (16) and activated macrophages also secrete cytokines like interleukin (IL)-12, which in turn stimulate Th1-type T cells to secrete IFN-γ and IL-2, activating other resting macrophages in an upward spiral. (17,18) We previously...

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Impact of PTEN expression on the outcome of hepatitis C virus‐positive cirrhotic hepatocellular carcinoma patients: Possible relationship with COX II and inducible nitric oxide synthase

Cited by 56 publications

References 28 publications

Immunohistochemical Expression of Components of the Akt-mTORC1 Pathway is Associated with Hepatocellular Carcinoma in Patients with Chronic Liver Disease

Immunohistochemical Expression of Components of the Akt-mTORC1 Pathway is Associated with Hepatocellular Carcinoma in Patients with Chronic Liver Disease

Effects and mechanisms of silibinin on human hepatoma cell lines

Depression of T cell‐mediated immunity reduces sulfadimethoxine‐induced capsular inflammation and inhibits associated development of invasive thyroid follicular cell carcinomas in rats

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