Metallothionein gene expression is altered in oral cancer and may predict metastasis and patient outcomes

Brazão–Silva, Marco Túllio; Rodrigues, Maria Isabel; Eisenberg, A.; Dias, Fernando Luiz; Castro, L.; Nunes, Fábio Daumas; Faria, Paulo Rogério de; Cardoso, Sérgio Vitorino; Loyola, Adriano Mota; Sousa, Suzana Orsini Machado de

doi:10.1111/his.12660

Cited by 22 publications

(10 citation statements)

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“…For example, zinc ions induced strong transcription of MT-1G , but not MT-1A genes, whereas nickel ions caused MT-1G expression exclusively. Inducer-specific expression of MT-1 genes has been noted in other cell types [34,44,45,46,47], supporting the hypothesis that individual isoforms have very selective metal ion sequestering functions [5,6,22,39,40,84]. Western blotting revealed that cadmium was the most potent inducer of MT-1A protein expression, whereas MT-1M protein expression was highly specific to cadmium, revealing the potential of both as biomarkers of cadmium exposure.…”

Section: Discussionmentioning

confidence: 69%

Specificity of the Metallothionein-1 Response by Cadmium-Exposed Normal Human Urothelial Cells

McNeill

Mason

Hodson

et al. 2019

IJMS

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Occupational and environmental exposure to cadmium is associated with the development of urothelial cancer. The metallothionein (MT) family of genes encodes proteins that sequester metal ions and modulate physiological processes, including zinc homeostasis. Little is known about the selectivity of expression of the different MT isoforms. Here, we examined the effect of cadmium exposure on MT gene and isoform expression by normal human urothelial (NHU) cell cultures. Baseline and cadmium-induced MT gene expression was characterized by next-generation sequencing and RT-PCR; protein expression was assessed by Western blotting using isoform-specific antibodies. Expression of the zinc transporter-1 (SLC30A1) gene was also assessed. NHU cells displayed transcription of MT-2A, but neither MT-3 nor MT-4 genes. Most striking was a highly inducer-specific expression of MT-1 genes, with cadmium inducing transcription of MT-1A, MT-1G, MT-1H, and MT-1M. Whereas MT-1G was also induced by zinc and nickel ions and MT-1H by iron, both MT-1A and MT-1M were highly cadmium-specific, which was confirmed for protein using isoform-specific antibodies. Protein but not transcript endured post-exposure, probably reflecting sequestration. SLC30A1 transcription was also affected by cadmium ion exposure, potentially reflecting perturbation of intracellular zinc homeostasis. We conclude that human urothelium displays a highly inductive profile of MT-1 gene expression, with two isoforms identified as highly specific to cadmium, providing candidate transcript and long-lived protein biomarkers of cadmium exposure.

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Section: Discussionmentioning

confidence: 69%

Specificity of the Metallothionein-1 Response by Cadmium-Exposed Normal Human Urothelial Cells

McNeill

Mason

Hodson

et al. 2019

IJMS

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“…There are few reports of the association of these genes with prognosis in HCC or in other cancers. Previous studies indicate that downregulation of CXCL14 is associated with prognosis in gastric cancer patients [32], MT1X may aid in the prognostic discrimination of oral squamous cell carcinoma cases [33], and MARCO expression is associated with breast cancer survival and risk of recurrence [34]. …”

Section: Discussionmentioning

confidence: 99%

Microarray-based identification of genes associated with cancer progression and prognosis in hepatocellular carcinoma

Yin

Shu

Liu

et al. 2016

J Exp Clin Cancer Res

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BackgroundHepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths. The average survival and 5-year survival rates of HCC patients still remains poor. Thus, there is an urgent need to better understand the mechanisms of cancer progression in HCC and to identify useful biomarkers to predict prognosis.MethodsPublic data portals including Oncomine, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) profiles were used to retrieve the HCC-related microarrays and to identify potential genes contributed to cancer progression. Bioinformatics analyses including pathway enrichment, protein/gene interaction and text mining were used to explain the potential roles of the identified genes in HCC. Quantitative real-time polymerase chain reaction analysis and Western blotting were used to measure the expression of the targets. The data were analysed by SPSS 20.0 software.ResultsWe identified 80 genes that were significantly dysregulated in HCC according to four independent microarrays covering 386 cases of HCC and 327 normal liver tissues. Twenty genes were consistently and stably dysregulated in the four microarrays by at least 2-fold and detection of gene expression by RT-qPCR and western blotting showed consistent expression profiles in 11 HCC tissues compared with corresponding paracancerous tissues. Eleven of these 20 genes were associated with disease-free survival (DFS) or overall survival (OS) in a cohort of 157 HCC patients, and eight genes were associated with tumour pathologic PT, tumour stage or vital status. Potential roles of those 20 genes in regulation of HCC progression were predicted, primarily in association with metastasis. INTS8 was specifically correlated with most clinical characteristics including DFS, OS, stage, metastasis, invasiveness, diagnosis, and age.ConclusionThe significantly dysregulated genes identified in this study were associated with cancer progression and prognosis in HCC, and might be potential therapeutic targets for HCC treatment or potential biomarkers for diagnosis and prognosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0403-2) contains supplementary material, which is available to authorized users.

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“…MTs overexpression was frequently reported to be associated with poor prognosis in a wide range of human cancers, such as hepatocellular carcinoma, breast cancer, glioblastoma, oral cancer, and melanoma [23, 35–38]. Although the prognostic role of MTs in gastric cancer was also evaluated in several studies, it is still hard to conclude what exact value they possessed.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the antibodies used in many studies could not specify MT1 and MT2 isoform due to their physical-chemical homology [39]. This speculation seems to be verified by the phenomenon mentioned above that the change in MT1/2 protein expression was different from single MT isoforms and different MT isoform plays distinct function in cell activities [38, 39]. Although the antibodies specific to MT1A, MT1G, and MT3 were available in market [9, 40], distinguishing of MTs by using antibodies is even more tricky.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of MT Family Isoforms as Potential Biomarker for Predicting Progression and Prognosis in Gastric Cancer

Tong

Líu

et al. 2019

BioMed Research International

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Background. Metallothioneins (MTs) family comprises many isoforms, most of which are frequently dysregulated in a wide range of cancers. However, the expression pattern and exact role of each distinct MT family isoform which contributes to tumorigenesis, progression, and drug resistance of gastric cancer (GC) are still unclear. Methods. Publicly available databases including Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier plotter, SurvExpress, MethHC, cBioportal, and GeneMANIA were accessed to perform an integrated bioinformatic analysis and try to detect fundamental relationships between each MT family member and GC. Results. Bioinformatic data indicated that the mRNA expression of all MT family members was almost lowly expressed in GC compared with normal gastric tissue (P<0.05), and patients with reduced mRNA expression of each individual MT member had inconsistent prognostic value (OS, FP, PPS), which depended on the individual isoform of MT. A negative correlation between the methylation in promoter region of majority of MT members and their mRNA expression was detected from MethHC database (p<0.001). Data downloaded from TCGA revealed that MTs were rarely mutated in GC patients and MT2A was frequently regulated by other three genes (FOS, JUN, SP1) in GC patients. Conclusion. MTs were nearly downregulated, and distinct type of MT harbored different prognostic role in GC patients. Methylation in gene promoter region of MTs partially contributed to their reduced expression in GC. Our comprehensive analyses from multiple independent databases may further lead researches to explore MT-targeting reagents or potential diagnostic and prognostic markers for GC patients.

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Metallothionein gene expression is altered in oral cancer and may predict metastasis and patient outcomes

Abstract: Metallothionein mRNA expression is altered significantly in oral squamous cell carcinomas. The expression of MT1G, MT1X and MT3 may aid in the prognostic discrimination of OSCC cases.

Cited by 22 publications

References 50 publications

Specificity of the Metallothionein-1 Response by Cadmium-Exposed Normal Human Urothelial Cells

Specificity of the Metallothionein-1 Response by Cadmium-Exposed Normal Human Urothelial Cells

Microarray-based identification of genes associated with cancer progression and prognosis in hepatocellular carcinoma

Evaluation of MT Family Isoforms as Potential Biomarker for Predicting Progression and Prognosis in Gastric Cancer

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