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Clin Cancer Res. 2019 Feb 1;25(3):1050-1062. doi: 10.1158/1078-0432.CCR-18-1281. Epub 2018 Oct 9.

Transcription Factor Myeloid Zinc-Finger 1 Suppresses Human Gastric Carcinogenesis by Interacting with Metallothionein 2A.

Author information

1
College of Life Sciences & Bioengineering, School of Science, Beijing Jiaotong University, Beijing, China.
2
Cancer and Inflammation Program (CIP), Center for Cancer Research (CCR), National Cancer Institute (NCI), Frederick, Maryland.
3
Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital/Institute, Beijing, China.
4
Department of Gastroenterology, Army General Hospital of PLA, Beijing, China.
5
College of Basic Medical, Binzhou Medical University, Yantai, Shandong, China.
6
Zhengzhou KODIA Biotechnology Co. Ltd., Zhengzhou, Henan, China.
7
State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing, China.
8
Department of Oncology and Translational Medicine Center Baotou City Central Hospital, Baotou, Inner Mongolia, China.
9
Basic Research Program, Leidos Biomedical Research, Inc., Frederick, Maryland.
10
College of Life Sciences & Bioengineering, School of Science, Beijing Jiaotong University, Beijing, China. jqhuang@bjtu.edu.cn.
#
Contributed equally

Abstract

PURPOSE:

Metallothionein 2A (MT2A) suppresses the progression of human gastric cancer potentially through an "MT2A-NF-κB pathway" with unclear mechanisms. This study explored the role of a transcription factor, myeloid zinc-finger 1 (MZF1), in MT2A-NF-κB 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-κB 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.

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