title: Metallothionein MT1M is a tumor suppressor of human hepatocellular carcinomas.
abstract: Members of the metallothionein (MT) family are short, cysteine-rich proteins involved in metal metabolism and detoxification, suggesting that MT proteins protect cells from damage caused by electrophilic carcinogens and thereby constitute a critical surveillance system against carcinogenesis. However, the roles of MT proteins in human hepatocellular carcinoma (HCC) are not fully understood. We identified a member of the MT family, termed MT1M. MT1M is expressed in various normal tissues with the highest level in the liver. MT1M expression can be induced by heavy metals and protect Escherichia coli from heavy metal toxicity. However, MT1M expression markedly decreased in human HCC specimens. A methylation profiling analysis indicated that the MT1M promoter is methylated in the majority of HCC tumors examined. Moreover, restored expression of MT1M in the HCC cell line Hep3B, which lacks endogenous MT1M expression, suppressed cell growth in vitro and in vivo and augmented apoptosis induced by tumor necrosis factor α. Furthermore, stable expression of MT1M in Hep3B cells blocked tumor necrosis factor α-induced degradation of IκBα and transactivation of NF-κB. We conclude that MT1M is a novel member of the MT family. Frequent downregulation of MT1M in human HCC may contribute to liver tumorigenesis by increasing cellular NF-κB activity.
authors.affiliation: State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Mao
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Yu
authors.forename: Chenji
authors.initials: C
authors.lastname: Wang
authors.forename: Luhong
authors.initials: L
authors.lastname: Sun
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Zhang
authors.forename: Qianyi
authors.initials: Q
authors.lastname: Xiao
authors.forename: Dingding
authors.initials: D
authors.lastname: Han
authors.forename: Dingbing
authors.initials: D
authors.lastname: Han
authors.forename: Hexige
authors.initials: H
authors.lastname: Saiyin
authors.forename: Jingde
authors.initials: J
authors.lastname: Zhu
authors.forename: Taoyang
authors.initials: T
authors.lastname: Chen
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
authors.forename: Long
authors.initials: L
authors.lastname: Yu
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D008668:Metallothionein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000502:physiology; D011401:Promoter Regions, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D008668:Metallothionein