Metallothionein in human gastrointestinal cancer

Janssen, A. Miranda L.; Duijn, Wim van; Ruit, M.M. Oostendorp-van de; Kruidenier, Laurens; Bosman, C; Griffioen, G.; Lamers, C. B. H. W.; Krieken, J. Han J.M. van; Velde, Cornelis J.H. van de; Verspaget, Hein W.

doi:10.1002/1096-9896(2000)9999:9999<::aid-path712>3.0.co;2-z

Cited by 55 publications

(55 citation statements)

References 49 publications

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“…It has been observed that colorectal carcinogenesis is characterized by a significant decrease in MT expression (13). Conversely, in some conditions MT expression is consid-A B C D ered to be protective against cancer development or to indicate a better prognosis (14).…”

Section: Resultsmentioning

confidence: 99%

“…This proposal is supported by the observation that MT is expressed in a patchy pattern in the neoplastic gastrointestinal tissues, with positive parts located next to negative parts (13), and that there is a clonal variation of the cadmium response in human tumor cell lines that may be related to the MT expression (21). Further studies are needed to confirm and further define the relationship between the spread of MTEC and its role in colonic carcinogenesis in rats treated with nimesulide or infected with T. cruzi.…”

Section: Resultsmentioning

confidence: 99%

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Trypanosoma cruzi infection and/or administration of the nonsteroidal anti-inflammatory nimesulide increase the number of colonic crypts overexpressing metallothioneins in rat colon carcinogenesis

Escalante

Oliveira

Cunha

et al. 2006

Braz J Med Biol Res

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Trypanosoma cruzi infection and nonsteroidal anti-inflammatory drugs inhibit colorectal carcinogenesis by mechanisms not completely known and metallothionein proteins (MTs) may be involved in this process. Sixty-six male Wistar rats weighing 90 to 120 g were randomly divided into seven groups (GI to GVII). GI, GII and GIII animals were subcutaneously infected with 200,000 trypomastigote forms of the Y strain of T. cruzi. After 8 weeks, GI, GII, GIV, and GVI were injected with one weekly subcutaneous dose of 12 mg/kg dimethylhydrazine for 4 weeks. In sequence, GI, GIV and GV were treated with nimesulide (10 mg/kg per dose, five times per week for 8 weeks). Groups I, III, IV, and VI had 12 animals, and each of the other groups had 6 animals. All the animals were euthanized 8 weeks after the last dimethylhydrazine injection. The colons were fixed and processed for MT immunohistochemistry. The index of MT-overexpressing colonic crypts (MTEC) was estimated as the percentage of MT-stained crypts in relation to the total number of crypts scored. Five hundred crypts per animal were scored. Data were analyzed by the Kruskal-Wallis test followed by the Dunn test. There was an increase in MTEC index in the groups either infected with T. cruzi or treated with nimesulide or both infected and treated when compared to control (401, 809, and 1011%, respectively). We suggest that the increased formation of MTEC may be related to the protection against carcinogenesis provided both by T. cruzi infection and nimesulide.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Trypanosoma cruzi infection and/or administration of the nonsteroidal anti-inflammatory nimesulide increase the number of colonic crypts overexpressing metallothioneins in rat colon carcinogenesis

Escalante

Oliveira

Cunha

et al. 2006

Braz J Med Biol Res

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“…Fresh histologically normal tissue specimens of 79 patients (21 females and 58 males, mean age 66 years, range 35 -91 years) who underwent resection for primary gastric adenocarcinoma at the department of Oncologic Surgery of the Leiden University Medical Center were collected prospectively, as described before (Janssen et al, 2002). Various clinico-pathological data were (re-)evaluated or collected from patient files by one gastroenterologist and one pathologist (Janssen et al, 2002).…”

Section: Patients and Study Designmentioning

confidence: 99%

“…Various clinico-pathological data were (re-)evaluated or collected from patient files by one gastroenterologist and one pathologist (Janssen et al, 2002). All carcinomas were classified according to the TNM classification (Hermanek and Sobin, 1992) and localisation as well as diameters of the tumours were registered.…”

Section: Patients and Study Designmentioning

confidence: 99%

Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer

et al. 2006

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Gastric cancers express enhanced levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Single-nucleotide polymorphisms (SNPs) in MMP and TIMP genes may be associated with disease susceptibility and might also affect their antigen expression. We studied the genotype distribution and allele frequencies of SNPs of MMP-2, -7, -8 and -9 and TIMP-1 and -2 in gastric cancer patients in relation to tumour progression, patient survival and tissue antigen expression. The genotype distribution and allele frequencies were similar in gastric cancer patients and controls, except for MMP-7 À181A4G . In addition, the genotype distribution of MMP-7 À181A4G was associated with Helicobacter pylori status (w 2 7.8, P ¼ 0.005) and tumour-related survival of the patients. Single-nucleotide polymorphism TIMP-2 303C4T correlated significantly with the WHO classification (w 2 5.9, P ¼ 0.03) and also strongly with tumour-related survival (log rank 11.74, P ¼ 0.0006). Single-nucleotide polymorphisms of MMP-2, -8, -9 and TIMP-1 were not associated with tumour-related survival. Only the gene promoter MMP-2 À1306C4T polymorphism correlated significantly with the protein level within the tumours. First-order dendrogram cluster analysis combined with Cox analysis identified the MMP-7 À181A4G and TIMP-2 303C4T polymorphism combination to have a major impact on patients survival outcome. We conclude that MMP-related SNPs, especially MMP-7 À181A4G and TIMP-2 303C4T , may be helpful in identifying gastric cancer patients with a poor clinical outcome.

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“…We and others have previously demonstrated that these proteins are progressively silenced during colorectal cancer progression, and that this is associated to poorer patient survival. (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

Arriaga

Greco

Mordoh

et al. 2014

Molecular Cancer Therapeutics

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Metallothioneins (MT) are a family of low molecular weight proteins that are silenced during colorectal cancer progression, mainly through epigenetic mechanisms, and this loss is associated with poor survival. In this article, we show that overexpression of the MT1G isoform sensitizes colorectal cell lines to the chemotherapeutic agents oxaliplatin (OXA) and 5-fluorouracil (5-FU), in part through enhancing p53 and repressing NF-kB activity. Despite being silenced, MTs can be reinduced by histone deacetylase inhibitors such as trichostatin A and sodium butyrate. In fact, this induction contributes to the cytotoxicity of these agents, given that silencing of MTs by siRNAs reduces their growth-inhibitory activities. Zinc ions also potently enhance MT expression and are cytotoxic to cancer cells. We show for the first time that OXA and 5-FU induce higher levels of intracellular labile zinc, as measured using the fluorescent probe FLUOZIN-3, and that such zinc contributes to the activation of p53 and repression of NF-kB. Addition of zinc enhanced growth inhibition by OXA and 5-FU, and was also capable of resensitizing 5-FU-resistant cell lines to levels comparable with sensitive cell lines. This effect was MT independent because silencing MTs did not affect zinc cytotoxicity. In conclusion, we show that MT induction and zinc administration are novel strategies to sensitize colorectal cancer cells to presently utilized chemotherapeutic agents. Mol Cancer Ther; 13(5); 1369-81. Ó2014 AACR.

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Metallothionein in human gastrointestinal cancer

Cited by 55 publications

References 49 publications

Trypanosoma cruzi infection and/or administration of the nonsteroidal anti-inflammatory nimesulide increase the number of colonic crypts overexpressing metallothioneins in rat colon carcinogenesis

Trypanosoma cruzi infection and/or administration of the nonsteroidal anti-inflammatory nimesulide increase the number of colonic crypts overexpressing metallothioneins in rat colon carcinogenesis

Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer

Metallothionein 1G and Zinc Sensitize Human Colorectal Cancer Cells to Chemotherapy

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