p21/waf1/cip1 in Gastric Cancer: Associations with Histopathological Subtypes, Lymphonodal Metastasis, Prognosis and p53 Status

Baldus, Stephan; Schneider, Paul M.; Mönig, Stefan P.; Zirbes, T. K.; Fromm, Susanne; Meyer, Willy; Glossmann, Jan-Peter; Schüler, Susanne; Thiele, Jüergen; Hölscher, A. H.; Dienes, Hans Peter

doi:10.1080/003655201750305512

Cited by 16 publications

(14 citation statements)

References 27 publications

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“…The aberrant expression of p21 has been documented in gastric cancer (Baas et al, 1998;Craanen et al, 1999;Baldus et al, 2001). However, the mechanism responsible for its aberrant expression is not clear.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells

et al. 2004

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Both heme oxygenase-1 (HO-1) and p21 WAF1/Cip1 (p21) are involved in the pathogenesis of human cancer and their functions are closely associated with apoptosis. However, how these two molecules regulate apoptosis in human gastric cancer is unknown. In this study, we studied how HO-1 and p21 were regulated in two gastric cancer cell lines, MKN-45 with wild p53 and MKN-28 with mutant p53. The cells were treated with hemin and cadmium to induce HO-1. The result showed that HO-1 protein was significantly induced by hemin and cadmium in both cells tested. Following the HO-1 expression, p21 level was also markedly induced. The cells with increased HO-1 and p21 showed obviously resistantance to apoptotic stimuli. The levels of HO-1 and p21 induced were significantly inhibited by p38 mitogen-activated protein kinase (p38 MAPK) inhibitor (SB203580) and extracellular-regulated kinase (ERK) inhibitor (PD098059). Parallel to decreased HO-1 and p21 expression, the kinase inhibitors also significantly attenuated the resistance of the cells to apoptosis. The elevated HO-1 and p21 was further found to be associated with increase activity of the nuclear NFjB and the inhibition of NF-jB led to the block of their induction. The elevated HO-1 and p21 were also demonstrated to be related to increased cellular inhibitor of caspase inbitory protein-2 (c-IAP2) and decreased caspapse-3 activity. It was noted that the above changes observed were not different between MKN-45 and MKN-28 cells, suggesting the functions of HO-1 and p21 were irrespective of the status of p53. In conclusion, we demonstrate that the resistance to apoptosis in gastric cancer cells with elevated HO-1 and p21 is independent of p53 status in a p38 MAPK-and ERK-mediated pathway with elevated c-IAP2 and decreased caspase-3 activity and that this pathway is sensitive to the inhibition of NF-jB.

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Section: Introductionmentioning

confidence: 99%

Upregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells

et al. 2004

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“…P53 plays a prominent role in cancer by deregulating apoptosis (44). In addition, p21 is downregulated or lost in several cancer types with its inhibitory control over the cell cycle (45,46). GAS5 exerts its effect in bladder cancer partly by regulating CDK6, since knockdown of GAS5 increased CDK6 mRNA and protein levels (27,28).…”

Section: Molecular Mechanism and Action Of Gas5mentioning

confidence: 99%

Long non-coding RNA growth arrest-specific transcript 5 in tumor biology

2015

Oncology Letters

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Abstract. The recognition of the biological relevance of long non-coding RNA (lncRNA) molecules has only recently been recognized as one of the most significant advances in contemporary molecular biology. A growing body of evidence indicates that lncRNAs act not only as the intermediary between DNA and protein but also as significant protagonists of cellular functions. The dysregulation of lncRNAs has increasingly been linked to numerous human diseases, particularly cancers. Recent studies have demonstrated that the lncRNA growth arrest-specific transcript 5 (GAS5) was pervasively downexpressed in most human cancers compared with non-cancerous adjacent tissues including gastric, breast, lung and prostate cancer. In addition, patients with decreased GAS5 expression have a significantly poorer prognosis than those with higher expression. Furthermore, GAS5 is involved in the control of cell apoptosis, proliferation, metastasis, angiogenesis, DNA repair and tumor cell metabolism. This review provides an overview of the current knowledge concerning the role of GAS5 in tumor expression and biology function.

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“…The sections were boiled in EDTA buffer (pH 9.0) for 20 min and then incubated with the primary antibody p27 at a dilution of 1:25 for 30 min at room temperature. For Skp2 immunostaining, an enhanced biotin-avidin method was used, as described earlier (29). For antigen retrieval, the slides were boiled in an autoclave in EDTA buffer (pH 8.0) for 10 min.…”

Section: And 5 ¶-Ggtccttttcaccagcaagct-3 ¶ (Hprt1-reverse)mentioning

confidence: 99%

High Skp2 Expression Characterizes High-Risk Neuroblastomas Independent of MYCN Status

Westermann

Henrich

Wei

et al. 2007

Clinical Cancer Research

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Purpose: Amplified MYCN oncogene defines a subgroup of neuroblastomas with poor outcome. However, a substantial number of MYCN single-copy neuroblastomas exhibits an aggressive phenotype similar to that of MYCN-amplified neuroblastomas even in the absence of high MYCN mRNA and/or protein levels. Experimental Design: To identify shared molecular mechanisms that mediate the aggressive phenotype in MYCN-amplified and single-copy high-risk neuroblastomas, we defined genetic programs evoked by ectopically expressed MYCN in vitro and analyzed them in high-risk versus low-risk neuroblastoma tumors (n = 49) using cDNA microarrays. Candidate gene expression was validated in a separate cohort of 117 patients using quantitative PCR, and protein expression was analyzed in neuroblastoma tumors by immunoblotting and immunohistochemistry. Results: We identified a genetic signature characterized by a subset of MYCN/MYC and E2F targets, including Skp2, encoding the F-box protein of the SCF Skp2 E3-ligase, to be highly expressed in high-risk neuroblastomas independent of amplified MYCN. We validated the findings for Skp2 and analyzed its expression in relation to MYCN and E2F-1 expression in a separate cohort (n = 117) using quantitative PCR. High Skp2 expression proved to be a highly significant marker of dire prognosis independent of both MYCN status and disease stage, on the basis of multivariate analysis of event-free survival (hazard ratio, 3.54; 95% confidence interval, 1.56-8.00; P = 0.002). Skp2 protein expression was inversely correlated with expression of p27, the primary target of the SCF Skp2 E3-ligase, in neuroblastoma tumors. Conclusion: Skp2 may have a key role in the progression of neuroblastomas and should make an attractive target for therapeutic approaches.

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p21/waf1/cip1 in Gastric Cancer: Associations with Histopathological Subtypes, Lymphonodal Metastasis, Prognosis and p53 Status

Abstract: These features show an association of p21 over-expression with certain clinico-pathological parameters of gastric cancer. In this context, our data suggest that p21 immunoreactivity in more than 5% of the tumour cells has a predictive value for the course of adenocarcinoma of the stomach.

Cited by 16 publications

References 27 publications

Upregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells

Upregulation of heme oxygenase-1 and p21 confers resistance to apoptosis in human gastric cancer cells

Long non-coding RNA growth arrest-specific transcript 5 in tumor biology

High Skp2 Expression Characterizes High-Risk Neuroblastomas Independent of MYCN Status

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