Overexpression of DNA damage-induced 45 α gene contributes to esophageal squamous cell cancer by promoter hypomethylation

Wang, Bao xiang; Yin, Bang Liang; He, Bin; Chen, Chen; Zhao, Ming; Zhang, Wei xing; Xia, Zhen Kun; Pan, Yi; Tang, Jing; Zhou, Xin min; Yin, Ning

doi:10.1186/1756-9966-31-11

Cited by 35 publications

(24 citation statements)

References 40 publications

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“…However, as few studies have described the mechanisms mediating GADD45A expression in ESCC, it is not known whether p53 regulates GADD45A expression in this cancer type (22). Notably, the present study found that GADD45A, but not p53, was able to predict the prognosis of patients with ESCC.…”

Section: Discussionsupporting

confidence: 54%

GADD45A expression is correlated with patient prognosis in esophageal cancer

et al. 2015

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Abstract. The prognosis of patients with esophageal cancer remains poor, and the tumor-node-metastasis classification system is not sufficient for predicting patient prognoses. Therefore, the identification of novel predictive markers for esophageal cancer is required. The present study investigated the clinicopathological significance of growth arrest and DNA damage-inducible 45α (GADD45A) and p53 in resectable esophageal squamous cell carcinoma (ESCC). The study consisted of 62 patients with esophageal cancer who underwent surgery between 2001 and 2007. The expression of the GADD45A gene product (GADD45A) and the p53 protein was analyzed by immunohistochemistry. The correlations among GADD45A expression, clinicopathological factors and prognosis were then analyzed in the patients with ESCC. GADD45A and p53 were expressed in 56.5% (35/62) and 48.4% (30/62) of patients, respectively. The expression of GADD45A did not show a marked correlation with that of p53. However, GADD45A expression correlated with pathological stage (stage 0-I vs. stages II-IV; P=0.014) and did not correlate with the tumor (T) or node (N) status. Furthermore, patients who were positive for GADD45A exhibited a significantly higher survival rate than those who were negative for GADD45A (log-rank test, P=0.009). Multivariate analysis indicated that T status, N status and GADD45A expression were significant variables predicting survival (hazard ratio, 2.486; 95% confidence interval, 1.168-5.290; P=0.018). Overall, GADD45A expression significantly affected the survival of patients with ESCC, and the reduced expression of GADD45A was correlated with a poor prognosis following curative surgery in these patients. IntroductionThe prognosis of esophageal cancer patients remains poor, emphasizing the requirement for the development of novel treatment strategies. At present, the overall 5-year survival rate is <50%, despite the use of multimodality therapies. Numerous patients, even those with early-stage disease, develop local recurrence of tumors or distant metastasis within a short time period after surgery. To develop novel treatment strategies, it is important to understand the biological behavior of esophageal cancer. Recent studies have found that a number of genes and molecules show involvement in the origin and/or progression of esophageal cancer, including tumor protein p53 (1), deleted in esophageal cancer 1 (2), deleted in colorectal cancer (3), deleted in lung cancer 1 (4), cyclin D1 (5), adenomatous polyposis coli (6) and survivin (7). However, the exact mechanisms underlying esophageal squamous cell carcinoma (ESCC) development and progression remain unclear.The p53 gene is required for the proper induction of the G 1 checkpoint and functions to upregulate growth arrest and DNA damage-inducible 45α (GADD45A) and WAF1/p21 expression (8). Additionally, GADD45A is a downstream mediator of p53 and is able to deactivate p53, thereby contributing to cell cycle regulation through binding with cyclin-dependent kinases and proliferating cell nuc...

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Section: Discussionsupporting

confidence: 54%

GADD45A expression is correlated with patient prognosis in esophageal cancer

et al. 2015

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“…Global methylation levels were measured using a Methylamp Global DNA Methylation Quantification Ultra kit (Epigentek Group Inc., New York, NY, USA) as previously described . According to the manufacturer's instructions, DNA is immobilized to the strip well specifically coated with a DNA affinity substance.…”

Section: Methodsmentioning

confidence: 99%

Homocysteine induces cytotoxicity and proliferation inhibition in neural stem cells via DNA methylation in vitro

et al. 2014

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Mild to moderate hyperhomocysteinemia has been implicated in neurodevelopmental disorders and neurodegenerative diseases in human studies. Although the molecular mechanisms underlying the effects of homocysteine (Hcy) neurotoxicity on the nervous system are not yet fully understood, inhibition of neural stem cell (NSC) proliferation and alterations in DNA methylation may be involved. The aim of the present study was to characterize the effects of Hcy on DNA methylation in NSCs, and to explore how Hcy-induced changes in DNA methylation patterns affect NSC proliferation. We found that D,L-Hcy (30-1000 lM) but not L-cysteine inhibited cell proliferation and reduced levels of global DNA methylation in NSCs from neonatal rat hippocampus and increased cell injury. High levels of Hcy also induced an increase in S-adenosylhomocysteine (SAH), a decrease in the ratio of S-adenosylmethionine (SAM) to SAH, and a reduction in protein expression of the DNA methyltransferases DNMT1, DNMT3a and DNMT3b and their enzymatic activity. Moreover, the DNMT inhibitor zebularine reduced the global DNA methylation level and inhibited NSC proliferation. Our results suggest that alterations in DNA methylation may be an important mechanism by which high levels of Hcy inhibit NSC viability in vitro. Hcy-induced DNA hypomethylation may be caused by a reduction in the DNMT activity which is regulated by the cellular concentrations of SAM and SAH, or their protein expression levels. Our results also suggest that Hcy may play a role in the pathogenesis of certain nervous system diseases via a molecular mechanism that involves negative regulation of NSC proliferation and alterations in DNA methylation.

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“…50 According to the manufacturer's instructions, the methylated fraction of DNA can be recognized by a 5-methylcytosine antibody and quantified through an ELISA-like reaction. The amount of methylated DNA is proportional to the OD intensity.…”

Section: Methodsmentioning

confidence: 99%

Early methyl donor deficiency may induce persistent brain defects by reducing Stat3 signaling targeted by miR-124

et al. 2013

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The methyl donors folate (vitamin B9) and vitamin B12 are centrepieces of the one-carbon metabolism that has a key role in transmethylation reactions, and thus in epigenetic and epigenomic regulations. Low dietary intakes of folate and vitamin B12 are frequent, especially in pregnant women and in the elderly, and deficiency constitutes a risk factor for various diseases, including neurological and developmental disorders. In this respect, both vitamins are essential for normal brain development, and have a role in neuroplasticity and in the maintenance of neuronal integrity. The consequences of a methyl donor deficiency (MDD) were studied both in vivo in rats exposed in utero, and in vitro in hippocampal progenitors (H19-7 cell line). Deficiency was associated with growth retardation at embryonic day 20 (E20) and postnatally with long-term brain defects in selective areas. mRNA and protein levels of the transcription factor Stat3 were found to be decreased in the brains of deprived fetuses and in differentiating progenitors (62 and 48% for total Stat3 protein, respectively), along with a strong reduction in its phosphorylation at both Tyr705 and Ser727 residues. Vitamin shortage also affected upstream kinases of Stat3 signaling pathway (phospho-Erk1/2, phospho-Src, phospho-JNK, and phospho-p38) as well as downstream target gene products (Bcl-2 and Bcl-xL), thus promoting apoptosis. Conversely, the expression of the Stat3 regulator miR-124 was upregulated in deficiency conditions (≥65%), and its silencing by using siRNA partly restored Stat3 signaling in hippocampal neurons by increasing specifically the phosphorylation of Erk1/2 and Src kinases. Furthermore, miR-124 siRNA improved the phenotype of deprived cells, with enhanced neurite outgrowth. Taken together, our data suggest that downregulation of Stat3 signaling by miR-124 would be a key factor in the deleterious effects of MDD on brain development.

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Overexpression of DNA damage-induced 45 α gene contributes to esophageal squamous cell cancer by promoter hypomethylation

Cited by 35 publications

References 40 publications

GADD45A expression is correlated with patient prognosis in esophageal cancer

GADD45A expression is correlated with patient prognosis in esophageal cancer

Homocysteine induces cytotoxicity and proliferation inhibition in neural stem cells via DNA methylation in vitro

Early methyl donor deficiency may induce persistent brain defects by reducing Stat3 signaling targeted by miR-124

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