TitleTranscription Factor Myeloid Zinc-Finger 1 Suppresses Human Gastric Carcinogenesis by Interacting with Metallothionein 2A
AuthorsLin, Shuye
Wang, Xiaoyue
Pan, Yuanming
Tian, Rongmeng
Lin, Bonan
Jiang, Guosheng
Chen, Keqiang
He, Yuqi
Zhang, Lulu
Zhai, Wanli
Jin, Peng
Yang, Lang
Li, Guoqiang
Wu, Yun
Hu, Jiang
Gong, Wanghua
Chang, Zhijie
Sheng, Jian-qiu
Lu, Youyong
Wang, Ji Ming
Huang, Jiaqiang
AffiliationBeijing Jiaotong Univ, Sch Sci, Coll Life Sci & Bioengn, Beijing, Peoples R China
NCI, CIP, Ctr Canc Res, Frederick, MD 21701 USA
Peking Univ, Canc Hosp Inst, Lab Mol Oncol, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing, Peoples R China
Army Gen Hosp PLA, Dept Gastroenterol, Beijing, Peoples R China
Binzhou Med Univ, Coll Basic Med, Yantai, Shandong, Peoples R China
Zhengzhou KODIA Biotechnol Co Ltd, Zhengzhou, Henan, Peoples R China
Tsinghua Univ, Sch Med, State Key Lab Membrane Biol, Beijing, Peoples R China
Baotou City Cent Hosp, Dept Oncol, Baotou, Inner Mongolia, Peoples R China
Baotou City Cent Hosp, Translat Med Ctr, Baotou, Inner Mongolia, Peoples R China
Leidos Biomed Res Inc, Basic Res Program, Frederick, MD USA
Issue Date2019
AbstractPurpose: 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.
Appears in Collections:北京肿瘤医院

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