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

Purpose: Metallothionein 2A (MT2A) suppresses the progression of human gastric cancer (GC) 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 GC. Experimental Design: MZF1 expression and function in GC were investigated in vitro and in vivo. The relationship between MZF1 and MT2A was determined by gain- and loss-of-function assays in GC cells and an immortalized gastric cell line GES-1. The prognostic value of MZF1 expression in association with MT2A was evaluated using immunohistochemistry in two cohorts. Results: MZF1 was epigenetically silenced in human GC cell lines and primary tumors. Overexpression of MZF1 in GC 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 co-localized in the nuclei of GES-1 cells to target the promoter of NFKB 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-GC effects by complexing with MZF1 to target NFKBIA. MT2A/MZF1 may serve as valuable prognostic markers and novel therapeutic targets for human GC.