Transcription Factor Myeloid Zinc-Finger 1 Suppresses Human Gastric Carcinogenesis by Interacting with Metallothionein 2A
Transcription Factor Myeloid Zinc-Finger 1 Suppresses Human Gastric Carcinogenesis by Interacting with Metallothionein 2A
复制标题
转录因子骨髓锌指 1 通过与金属硫蛋白 2A 相互作用抑制人类胃癌发生
DOI：
10.1158/1078-0432.ccr-18-1281
复制
发表时间：
2019-02-01
影响因子：
11.5
通讯作者：
Huang, Jiaqiang
中科院分区：
文献类型：
--
作者：
Lin, Shuye;Wang, Xiaoyue;Huang, Jiaqiang
目的：金属硫蛋白2A（Metallothionein 2A，MT 2A）可能通过“MT 2A-NF-κ B通路”抑制胃癌的发生发展，但其机制尚不清楚。本研究旨在探讨转录因子髓样锌指蛋白1（myeloid zinc finger 1，MZF 1）在MT 2A-NF-kappa B通路中的作用及其在胃癌中的临床意义。通过胃癌细胞和永生化胃细胞系GES-1中的功能获得和功能丧失测定来确定MZF 1和MT 2A之间的关系。MZF 1表达与MT 2A的预后价值进行了评估，使用IHC在两个cohols.Results：MZF 1在人胃癌细胞系和原发性肿瘤的表观遗传沉默。MZF 1在胃癌细胞中的过表达抑制细胞增殖和迁移，以及裸鼠异种移植瘤的生长。MZF 1的敲低将GES-1细胞转化为恶性表型，其特征在于细胞生长和迁移增加。从机制上讲，MZF 1在GC和GES-1细胞中通过MT 2A异位表达或用大蒜衍生化合物二烯丙基三硫化物（DATS）处理后诱导而上调。与MT 2A相关的MZF 1共定位于GES-1细胞的细胞核中，以靶向NF-κ B抑制剂α（NFKBIA）的启动子。临床上，MT 2A和MZF 1在经历胃恶性转化的临床标本中进行性下调。结论：MT 2A通过与MZF 1结合靶向NFKBIA发挥抗胃癌作用。MT 2A/MZF 1可能是一个有价值的胃癌预后指标和新的治疗靶点。
Purpose: Metallothionein 2A (MT2A) suppresses the progression of human gastric cancer potentially through an "MT2A-NF-kappa B pathway" with unclear mechanisms. This study explored the role of a transcription factor, myeloid zinc-finger 1 (MZF1), in MT2A-NF-kappa B pathway and its clinical significance in gastric cancer.Experimental Design: MZF1 expression and function in gastric cancer were investigated in vitro and in vivo. The relationship between MZF1 and MT2A was determined by gain-of-function and loss-of-function assays in gastric cancer cells and an immortalized gastric cell line GES-1. The prognostic value of MZF1 expression in association with MT2A was evaluated using IHC in two cohorts.Results: MZF1 was epigenetically silenced in human gastric cancer cell lines and primary tumors. Overexpression of MZF1 in gastric cancer cells suppressed cell proliferation and migration, as well as the growth of xenograft tumors in nude mice. Knocking-down of MZF1 transformed GES-1 cells into a malignant phenotype characterized by increased cell growth and migration. Mechanistically, MZF1 was upregulated in both GC and GES-1 cells by MT2A ectopically expressed or induced upon treatment with a garlic-derived compound, diallyl trisulfide (DATS). MZF1 associated with MT2A was colocalized in the nuclei of GES-1 cells to target the promoter of NF-kappa B inhibitor alpha (NFKBIA). Clinically, MT2A and MZF1 were progressively downregulated in clinical specimens undergoing gastric malignant transformation. Downregulation of MT2A and MZF1 was significantly correlated with poorer patient prognosis.Conclusions: MT2A exerts its anti-gastric cancer effects by complexing with MZF1 to target NFKBIA. MT2A/MZF1 may serve as a valuable prognostic marker and a novel therapeutic target for human gastric cancer.