Metallothionein and apoptosis in primary human hepatocellular carcinoma and metastatic adenocarcinoma

Dx, Deng; Chakrabarti, Subrata; Mp, Waalkes; Mg, Cherian

doi:10.1046/j.1365-2559.1998.00348.x

Cited by 45 publications

(24 citation statements)

References 35 publications

(46 reference statements)

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“…In hepatocellular carcinoma, a decrease in the intensity of immunohistochemical staining has been reported for metallothioneins. 36,37 Metallothioneins were also found to be downregulated in hepatocellular carcinoma in a global mRNA expression analysis by Okabe et al, 30 concordant with our results. In patients suffering from hepatocellular carcinoma, metallothioneins were measured in serum, and the concentration correlated inversely with the grade of differentiation of hepatocellular carcinoma.…”

Section: -31supporting

confidence: 91%

Loss of 13q is associated with genes involved in cell cycle and proliferation in dedifferentiated hepatocellular carcinoma

et al. 2008

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Dedifferentiation of hepatocellular carcinoma implies aggressive clinical behavior and is associated with an increasing number of genomic alterations, eg deletion of 13q. Genes directly or indirectly deregulated due to these genomic alterations are mainly unknown. Therefore this study compares array comparative genomic hybridization and whole genome gene expression data of 23 well, moderately, or poorly dedifferentiated hepatocellular carcinoma, using unsupervised hierarchical clustering. Dedifferentiated carcinoma clearly branched off from well and moderately differentiated carcinoma (Po0.001 v 2 -test). Within the dedifferentiated group, 827 genes were upregulated and 33 genes were downregulated. Significance analysis of microarrays for hepatocellular carcinoma with and without deletion of 13q did not display deregulation of any gene located in the deleted region. However, 531 significantly upregulated genes were identified in these cases. A total of 6 genes (BIC, CPNE1, RBPMS, RFC4, RPSA, TOP2A) were among the 20 most significantly upregulated genes both in dedifferentiated carcinoma and in carcinoma with loss of 13q. These genes are involved in cell-cycle control and proliferation. Of 33 downregulated genes in the dedifferentiated subgroup, 4 metallothioneins had the lowest fold change, most probably mediated through inactivation of C/EBPa by the PI3K/AKT cascade. In conclusion dedifferentiation of hepatocellular carcinoma is associated with upregulation of genes involved in cell-cycle control and proliferation. Notably, a significant portion of these genes is also upregulated in carcinoma with deletion of 13q. As no downregulated genes were identified and microRNAs (mir-621, mir-16-1, mir-15a) are located within the deleted region of 13q and may be lost, we speculate that these miRNAs may induce the upregulation of critical cell-cycle control genes.

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Section: -31supporting

confidence: 91%

Loss of 13q is associated with genes involved in cell cycle and proliferation in dedifferentiated hepatocellular carcinoma

et al. 2008

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“…Previously, a similar downregulation of MT expression has been reported in metastatic lymph nodes from human breast cancers [29]. Also, Deng et al [30]reported that the primary hepatocellular carcinomas showed moderate MT staining with a small number of apoptotic cells while metastatic adenocarcinomas showed no MT staining with a large number of apoptotic cells. Therefore, it seems that altered MT expression in the metastatic tumor is produced by some kind of phenotypic change due to the change in the tumor environment, or it might be possible that the MT-negative metastatic tumor cells are derived from a pool of heterogeneous cells with variable MT expression in the primary tumor.…”

Section: Discussionsupporting

confidence: 68%

Expression of Metallothionein in Colorectal Cancers and Synchronous Liver Metastases

Hishikawa¹,

Kohno²,

Ueda³

et al. 2001

Oncology

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The aim of this study is to clarify whether the expression of metallothionein (MT) is related with the malignant potential in primary colorectal cancer and/or synchronous liver metastasis. Immunohistochemical staining for MT was performed on the specimens of adenocarcinoma of the colon and rectum and its liver metastases in 34 patients treated with curative surgery, respectively. Expression of MT was compared with clinicopathological variables and patient survival. In patients with primary colorectal cancer, positive expression was found in 7 of 34 (20.6%) patients, but MT was not detected in any of the cases of liver metastases (0%; p = 0.0111). In the primary tumor, positive MT expression was significantly associated with a higher degree of lymph node involvement (mean ± SD: 48.4 ± 33.8 vs. 18.6 ± 24.4% in MT-positive and MT-negative tumors, respectively; p = 0.0122). The survival rate in the patients with MT-negative tumors was significantly better than that in those with MT-positive tumors as primary sites (p = 0.0198). MT expression in colorectal cancer may be a potential marker affecting lymph node metastases and may be a predictor of a poor prognosis, particularly in patients with synchronous liver metastases.

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“…Recently, some studies have suggested that the degree of MT expression may affect apoptotic processes in certain normal and tumor cells and the incidence of apoptosis may differ with alteration in MT expression. 33,34) Deng et al 35) reported a negative correlation of MT with the incidence of apoptotic cells in human primary hepatocellular carcinomas and metastases, possibly associated with inhibition of apoptotic transduction signals. Further, Penkowa et al 36) proposed that MT may inhibit apoptotic cell death in the central nervous system of female Lewis rats.…”

Section: Discussionmentioning

confidence: 99%

Significance of overexpression of metallothionein in mouse urinary bladder focal lesions induced by treatment with N‐butyl‐N‐(4‐hydroxybutyl)‐nitrosamine

Mitsuhashi¹,

Wanibuchi²,

Morimura³

et al. 2003

Cancer Science

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Metallothionein (MT) is expressed in various types of human tumors, including transitional cell carcinomas of the urinary bladder, but its biological significance remains unclear. In the present study, the role of MT in urinary bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) treatment was investigated using C57BL/6 mice. One hundred 5-week-old male C57BL/6 mice were divided into two groups, which were given drinking water with or without 0.05% BBN throughout the experimental period. Subgroups of ten animals from each group were sacrificed at weeks 5, 10, 15, 20 and 25, and urinary bladder samples were examined immunohistochemically for MT, proliferating cell nuclear antigen (PCNA) and apoptosis. MT was found to be abundant in normal-looking mucosa, but decreased with progression from precancerous lesions to invasive carcinoma in the urinary bladder obtained from BBN-treated mice. Lesions could be divided into MT-positive and negative. There was a tendency for greater MT expression in PCNA-positive lesions, while apoptosis was rather associated with MT-negativity. These data suggest that the overexpression of MT may play a role in mouse urinary bladder carcinogenesis. (Cancer Sci 2003; 94: 1052-1058 etallothionein (MT) is a ubiquitous, low-molecularweight protein with high contents of cysteine and metals, including cadmium, zinc and copper. It is expressed in a wide variety of organisms from yeast to human and is observed in most vertebrate tissues, being localized in both cytoplasm and nuclei of cells.1) Its biosynthesis can be induced by a number of factors, including heavy metals, various cytokines, growth factors, tumor promoters, glucocorticoid hormones and xenobiotics.2) However, the physiological significance of MT is not yet well understood, although its ability to sequester and dispense metal ions is thought to be important for regulation of cellular homeostasis and the functions of essential trace elements such as Zn and Cu, as well as in protection against toxicity of heavy metals, particularly cadmium.3) In addition, MT appears to promote the resistance of cells to not only some alkylating agents and chemotherapeutic metal compounds, such as cisplatin, chlorambucil and melphalan, 4) but also electrophilic mutagens such as N-methyl-N′-nitro-N-nitrosoguanidine and N-methyl-N-nitrosourea. 5) Interestingly, MT has also been implicated in protection against the cytotoxic effects of oxidative stress, because it is a potent hydroxyl radical scavenger.6) In vitro, MT protects cells against the cytotoxic and DNA-damaging effects of nitric oxide and the DNA-damaging effects of H 2 O 2 , 7) and also against radical-induced lipid peroxidation.8) It contributes to metalloregulation during cell growth and differentiation. 9)High levels of MT gene expression have been detected during the late stages of gestation and in the neonatal period.10) Enhanced synthesis of MT in rapidly proliferating tissues appears to suggest a link with cell growth. 4)In humans, functional MT isoforms are enco...

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Metallothionein and apoptosis in primary human hepatocellular carcinoma and metastatic adenocarcinoma

Abstract: These results suggest a relationship between absence of MT and appearance of APPC in human liver tumours, especially in metastatic adenocarcinomas.

Cited by 45 publications

References 35 publications

Loss of 13q is associated with genes involved in cell cycle and proliferation in dedifferentiated hepatocellular carcinoma

Loss of 13q is associated with genes involved in cell cycle and proliferation in dedifferentiated hepatocellular carcinoma

Expression of Metallothionein in Colorectal Cancers and Synchronous Liver Metastases

Significance of overexpression of metallothionein in mouse urinary bladder focal lesions induced by treatment with N‐butyl‐N‐(4‐hydroxybutyl)‐nitrosamine

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