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

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. 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. 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. 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.

Lin S ，Wang X ，Pan Y ，Tian R ，Lin B ，Jiang G ，Chen K ，He Y ，Zhang L ，Zhai W ，Jin P ，Yang L ，Li G ，Wu Y ，Hu J ，Gong W ，Chang Z ，Sheng JQ ，Lu Y ，Wang JM ，Huang J ... -  《-》

Epigenetic Upregulation of Metallothionein 2A by Diallyl Trisulfide Enhances Chemosensitivity of Human Gastric Cancer Cells to Docetaxel Through Attenuating NF-κB Activation.

Pan Y ，Lin S ，Xing R ，Zhu M ，Lin B ，Cui J ，Li W ，Gao J ，Shen L ，Zhao Y ，Guo M ，Wang JM ，Huang J ，Lu Y ... -  《-》

Metallothionein 2A inhibits NF-κB pathway activation and predicts clinical outcome segregated with TNM stage in gastric cancer patients following radical resection.

Pan Y ，Huang J ，Xing R ，Yin X ，Cui J ，Li W ，Yu J ，Lu Y ... -  《Journal of Translational Medicine》

miRNA-337-3p inhibits gastric cancer progression through repressing myeloid zinc finger 1-facilitated expression of matrix metalloproteinase 14.

Zheng L ，Jiao W ，Mei H ，Song H ，Li D ，Xiang X ，Chen Y ，Yang F ，Li H ，Huang K ，Tong Q ... -  《Oncotarget》

Clinical Significance of Myeloid Zinc Finger 1 Expression in the Progression of Gastric Tumourigenesis.

To investigate the clinical significance of myeloid zinc finger 1 (MZF1) expression in various gastric mucosal lesions including chronic superficial gastritis (CSG), chronic atrophic gastritis (CAG), intestinal metaplasia (IM), dysplasia (DYS) and gastric cancer (GC) in comparison with normal tissues and gastric cell lines. MZF1 protein expression was detected using immunohistochemical staining in 37 CSG, 88 CAG, 77 IM, 51 DYS, 165 GC and 8 normal tissue samples. Quantitative real-time PCR (qRT-PCR) and western blotting were used to detect the level of MZF1 in gastric cell lines, 15 normal tissues and 34 GC samples, as well as 2 groups of paired primary GC and adjacent normal samples. Reduced MZF1 expression was detected in most GC cells and tissues. Among the gastric tissues consisting of various stages of lesions (normal, CSG, CAG, IM, DYS and GC), MZF1 protein expression was downregulated in precancerous lesions and GC. The data from clinical analyses showed that decreased MZF1 expression was correlated with tumour invasion (p = 0.044), lymph node metastasis (p = 0.048) and poor prognosis of GC patients (p = 0.003). Moreover, MZF1 was identified as an independent prognostic biomarker for GC patients in multivariate Cox regression analysis (p = 0.009). Downregulation of MZF1 was associated with gastric tumourigenesis, which may be a novel early predictive and prognostic biomarker in GC patients.

Li GQ ，He Q ，Yang L ，Wang SB ，Yu DD ，He YQ ，Hu J ，Pan YM ，Wu Y ... -  《-》