Metallothionein 1M suppresses tumorigenesis in hepatocellular carcinoma

Fu, Chenglin; Pan, Bing; Pan, Juhua; Gan, Meifu

doi:10.18632/oncotarget.16521

Cited by 19 publications

(17 citation statements)

References 32 publications

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“…Downregulation of MT1M has been observed in hepatocellular, esophagus squamous cell carcinomas, breast, and other tumors and was associated with various clinicopathological parameters describing cancer aggressiveness (25)(26)(27). In this study, MT1M methylation was more frequently detected in tumors of larger size and higher Fuhrman grade, which is in accordance with previous observations in other tumors reporting its putative role in cancer progression (25,27,28).…”

Section: Discussionsupporting

confidence: 92%

DNA methylation of metallothionein genes is associated with the clinical features of renal cell carcinoma

et al. 2019

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Metallothioneins are low-weight cysteine-rich proteins responsible for metal ion homeostasis in a cell and, thus, capable of regulating cell proliferation and differentiation. Deregulation of metallothionein genes has been reported in various human tumors. However, their role in renal cell carcinoma (RCC) has been poorly investigated. In the present study, we aimed to evaluate the importance of promoter DNA methylation of selected metallothionein genes for RCC. Based on the initial analysis of kidney renal clear cell carcinoma dataset from The Cancer Genome Atlas, genes MT1E, MT1F, MT1G and MT1M were selected for qualitative methylation analysis in 30 tumors (including 10 multifocal cases), 10 pericancerous, and 30 non-cancerous renal tissues (NRT). Methylation of MT1E and MT1M was tumor-specific (P=0.0056 and P=0.0486, respectively) and showed moderate interfocal variation in paired tumor foci. Methylated promoter status of the two genes was associated with larger tumor size (P=0.0110 and P=0.0156, respectively). Furthermore, aberrant MT1E methylation was more frequent in tumors having necrotic zones (P=0.0449) or characterized with higher differentiation grade (P=0.0144), while MT1M was more commonly methylated in tumors with higher Fuhrman grade (P=0.0272). Only unmethylated MT1F promoter status was observed in all analyzed samples. Gene expression analysis (51 RCC and 9 NRT) revealed MT1G downregulation in tumors (P<0.0001), while lower MT1E expression levels were associated with the promoter methylation (P=0.0077). In clear cell RCC, MT1E, MT1G and MT1M expression was higher than that noted in other histological tumor subtypes (all P<0.0500). In addition, some associations were observed between metabolic syndrome-related clinical parameters and promoter methylation or gene expression. In conclusion, the present study revealed the potential role of MT1E and MT1M promoter methylation in RCC development.

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Section: Discussionsupporting

confidence: 92%

DNA methylation of metallothionein genes is associated with the clinical features of renal cell carcinoma

et al. 2019

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“…MTs consist of 16 functional MT isoforms that are divided into four subgroups (MT1, 2, 3 and 4). Noteworthily, increasing reports showed that MTs were involved in many physiological and pathophysiological processes of cancer, such as apoptosis, proliferation, metastasis and drug resistance 32–35 . It has been reported that MTs behaved as cancerogenic factors or tumor suppressors depending on the different cancer types.…”

Section: Discussionmentioning

confidence: 99%

“…While previous reports showed that expression of MT1 subgroup was downregulated due to promoter methylation in HCC 36,37 . Some other isoforms of MT1 were identified as tumor suppressors such as MT1M and MT1H in HCC 32,38 . Moreover, double deletion of MT1 and MT2 promotes diethylnitrosamine-induced hepatocarcinogenesis in mice 39 .…”

Section: Discussionmentioning

confidence: 99%

MT1G serves as a tumor suppressor in hepatocellular carcinoma by interacting with p53

Wang

Tan

et al. 2019

Oncogenesis

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Poor prognosis of hepatocellular carcinoma (HCC) patients is frequently associated with rapid tumor growth, recurrence and drug resistance. MT1G is a low-molecular weight protein with high affinity for zinc ions. In the present study, we investigated the expression of MT1G, analyzed clinical significance of MT1G, and we observed the effects of MT1G overexpression on proliferation and apoptosis of HCC cell lines in vitro and in vivo. Our results revealed that MT1G was significantly downregulated in tumor tissues, and could inhibit the proliferation as well as enhance the apoptosis of HCC cells. The mechanism study suggested that MT1G increased the stability of p53 by inhibiting the expression of its ubiquitination factor, MDM2. Furthermore, MT1G also could enhance the transcriptional activity of p53 through direct interacting with p53 and providing appropriate zinc ions to p53. The modulation of MT1G on p53 resulted in upregulation of p21 and Bax, which leads cell cycle arrest and apoptosis, respectively. Our in vivo assay further confirmed that MT1G could suppress HCC tumor growth in nude mice. Overall, this is the first report on the interaction between MT1G and p53, and adequately uncover a new HCC suppressor which might have therapeutic values by diminishing the aggressiveness of HCC cells.

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“…1). Finally, 22 reports were left in this meta-analysis, including one of oral cavity, [32] 1 of lung, [33] 1 of lymphocyte, [34] 2 of kidney, [35,36] 2 of bladder, [37,38] 2 of skin, [39,40] 2 of colon, [41,42] 3 of ovary, [43–45] 3 of liver [46–48] and 5 of breast. [49–53] In total, 2843 patients were enrolled in this meta-analysis, with 1517 cases in the MT negative/low group and 1326 cases in the MT high group (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Metallothioneins may be a potential prognostic biomarker for tumors

Wang

Xin²,

Lin³

et al. 2018

Medicine

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Background:Metallothioneins (MTs) were reported to be associated with many kinds of tumors’ prognosis, although MTs expression varied greatly among tumors. To assess the prognostic value of Metallothioneins (MTs) in different kinds of tumors, comprehensive literature search was conducted to perform a meta-analysis.Methods:Eligible studies were identified by PubMed, MEDLINE, Web of Science (WOS), the Cochrane Library of Systematic Reviews, EMBASE, China National Knowledge Infrastructure (CNKI), WANFANG database and SinoMed database up to December 2017, which was designed to assess the prognostic value of MTs in different kinds of tumors. The main endpoint events were overall survival (OS) and disease-free survival (DFS). Hazard ratios (HRs) and its variance were retrieved from the original studies directly or calculated using Engauge Digitizer version 4.1. Random or fixed effects model meta-analysis was employed depending on the heterogeneity. Publication bias was evaluated by funnel plots, Begg and Egger tests.Results:A total of 22 studies were enrolled in this meta-analysis, including 2843 tumor tissues (1517 were MTs negative/low, and 1326 were MTs high). Results showed that there was significant association between MTs expression and tumors’ OS (HR = 1.60; 95%CI 1.34∼1.92, P < .00001). Subgroup analysis showed that high level of MTs expression was associated with prolonged OS in liver cancer (HR = 0.65, 95%CI 0.48∼0.89, P = .007), but it was on the contrary in the tumor of ovary (HR = 1.47, 95%CI 1.01∼2.14, P = .04), bladder (HR = 1.71, 95%CI 1.21∼2.42, P = .002), intestine (HR = 3.13, 95%CI 1.97∼4.97, P < .00001), kidney (HR = 3.31, 95%CI 1.61∼6.79, P = .001). However, there was no significant association between MTs expression and OS in breast (HR = 1.02, 95%CI 0.69∼1.51, P = .93).Conclusions:MTs could be taken as a potential prognostic biomarker for tumors, and uniqueness of MTs prognostic value in liver cancer deserved further study.

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Metallothionein 1M suppresses tumorigenesis in hepatocellular carcinoma

Cited by 19 publications

References 32 publications

DNA methylation of metallothionein genes is associated with the clinical features of renal cell carcinoma

DNA methylation of metallothionein genes is associated with the clinical features of renal cell carcinoma

MT1G serves as a tumor suppressor in hepatocellular carcinoma by interacting with p53

Metallothioneins may be a potential prognostic biomarker for tumors

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