Downregulation of metallothionein-IIA expression occurs at immortalization

Duncan, Emma L.; Reddel, Roger R.

doi:10.1038/sj.onc.1202370

Cited by 22 publications

(12 citation statements)

References 38 publications

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“…Duncan et al reported that down-regulation of MT2A expression occurred upon immortalization, which implies that MT2A is down-regulated when human cells become immortal phenotypes, a key event in tumorigenesis [46]. …”

Section: Discussionmentioning

confidence: 99%

Metallothionein 2A inhibits NF-κB pathway activation and predicts clinical outcome segregated with TNM stage in gastric cancer patients following radical resection

et al. 2013

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BackgroundMetallothionein 2A (MT2A) as a stress protein, plays a protective role in gastric mucosal barrier. Its role in the development of gastric cancer (GC) is unclear. The mechanism of MT2A will be investigated in gastric tumorigenesis.MethodsMT2A expression was detected in 973 gastric specimens. The biological function was determined through ectopic expressing MT2A in vitro and in vivo. The possible downstream effectors of MT2A were investigated in NF-κB signaling. The protein levels of MT2A, IκB-α and p-IκB-α (ser32/36) expression were analyzed in a subset of 258 patients by IHC staining. The prognostic effects of MT2A, status of IκB-α and TNM stage were evaluated using the Kaplan-Meier method and compared using the log-rank test.ResultsDecreased MT2A expression was detected in cell lines and primary tumors of GC. In clinical data, loss of MT2A (MT2A + in Normal (n =171, 76.0%); Intestinal metaplasia (n = 118, 50.8%); GC (n = 684. 22.4%, P < 0.001)) was associated with poor prognosis (P < 0.001), advanced TNM stage (P = 0.05), and down-regulation of IκB-α expression (P < 0.001). Furthermore, MT2A was the independent prognostic signature segregated from the status of IκB-α and pathological features. In addition, MT2A inhibited cell growth through apoptosis and G2/M arrest, which negatively regulated NF-κB pathway through up-regulation of IκB-α and down-regulation of p-IκB-α and cyclin D1 expression.ConclusionsMT2A might play a tumor suppressive activity through inhibiting NF-κB signaling and may be a prognostic biomarker and potential target for individual therapy of GC patients.

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Section: Discussionmentioning

confidence: 99%

Metallothionein 2A inhibits NF-κB pathway activation and predicts clinical outcome segregated with TNM stage in gastric cancer patients following radical resection

et al. 2013

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“…The expression of human MT-IIA gene is drastically reduced in human colorectal tumors and cell lines derived from these tumors compared with normal tissues (17). Further, immortalization of human cells also causes reduction in MT expression (18). Interestingly, the common tumor suppressor genes (e.g., p53, Rb, and p16) are expressed in the rat hepatoma (19).…”

Section: Metals Toxicitymentioning

confidence: 93%

Suppression of metallothionein-I/II expression and its probable molecular mechanisms.

Jacob

Majumder

Ghoshal

2002

Environ Health Perspect

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Metallothionein (MT) promoter was methylated in rat hepatoma and in mouse lymphosarcoma cells by methylation of cytosine within the CpG dinucleotide region. After demethylation of MT-I promoter in mouse lymphosarcoma cells or in the transplanted rat hepatoma with 5-azacytidine, a potent inhibitor of DNA methyltransferase, the promoter was activated in response to heavy metal treatment. MT-I promoter was also suppressed in human prostate cancer lines PC3 and DU145, probably by promoter methylation, whereas cadmium induced MT-I in the human prostate cancer line LNCaP. In the prostate cancer lines where MT-I was suppressed, glutathione-S-transferase-pi (GST-pi) was expressed. On the contrary, GST-pi gene was repressed in the cell line where MT-I was induced, which suggests an inverse relationship between MT-I induction and GST-pi expression in some prostate cancer lines. The expressions of GST-pi and gamma-glutamyl cysteine synthase were also significantly higher (5- to 12-fold) in the lymphosarcoma cells and the hepatoma relative to the parental tissues. The higher expressions of these two genes suggest a compensatory mechanism in the cells where the gene for the antioxidant MT-I/II is not induced. MT-I/II may function as a growth suppressor either alone or in concert with other factor(s), and consequently their lack of expression could facilitate the tumor growth. In addition to suppression of MT-I/II expression by promoter methylation, the lack of MT induction could also be brought about by nuclear factor I (NFI), probably by interaction with the metal transcription factor MTF-1. An inverse relationship was observed between the level of NFI and MT-I expression in some cells, which suggests a role for NFI in the relatively low constitutive levels of MT-I expression in these cells.

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“…Interestingly, MT and MT-2a were also downregulated by the PA coal at 6 and 24 h treatment along with many other zinc-binding proteins. It has been shown that MT downregulation occurs when human cells become immortalized (Duncan & Reddel, 1999). No significant differences in levels of ferritin mRNA among samples were found, which was due to the high fluorescence readings of ferritin transcripts (saturation on the gene chips, data not shown).…”

Section: Discussionmentioning

confidence: 74%

Gene Expression of Primary Human Bronchial Epithelial Cells in Response to Coal Dusts with Different Prevalence of Coal Workers' Pneumoconiosis

Zhang

Wei

et al. 2003

Journal of Toxicology and Environmental Health, Part A

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Striking regional differences in the prevalence of coal workers' pneumoconiosis (CWP) have been observed but not fully understood. This study investigated the early biological responses of primary lung cells to treatment with coal dusts from various seams. High-density oligoarray technology (GeneChip, Affymetrix, Santa Clara, CA) was used to compile gene expression profiles of primary human bronchial epithelial cells to low concentrations (2 microg/cm(2)) of coals for 6 h or 24 h of treatment. Data showed that a total of 1050 out of 12,000 genes on the chip were altered by 2 coal dusts. The coal from the Pennsylvania (PA) coal-mine region with a high prevalence of CWP altered 908 genes, many more than the coal from Utah (UT) with a low prevalence of CWP, which affected 356 genes. Many genes decreased their expression levels in response to the PA coal at 6 h and/or 24 h of treatment. For example, transferrin receptor, a gene known to control cellular iron uptake, was downregulated in the cells treated with the iron-containing PA coal in order to protect cells from iron overload. The UT coal without bioavailable iron had no such effect. The downregulation patterns of genes were confirmed by reverse-transcription polymerase chain reaction (RT-PCR). This study is one of the first in profiling gene expressions of primary bronchial epithelial cells treated with coals from various seams, which may set stages for future studies on specific genes.

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Downregulation of metallothionein-IIA expression occurs at immortalization

Cited by 22 publications

References 38 publications

Metallothionein 2A inhibits NF-κB pathway activation and predicts clinical outcome segregated with TNM stage in gastric cancer patients following radical resection

Metallothionein 2A inhibits NF-κB pathway activation and predicts clinical outcome segregated with TNM stage in gastric cancer patients following radical resection

Suppression of metallothionein-I/II expression and its probable molecular mechanisms.

Gene Expression of Primary Human Bronchial Epithelial Cells in Response to Coal Dusts with Different Prevalence of Coal Workers' Pneumoconiosis

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