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

Abstract

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

Exosomes from mesenchymal stromal cells reduce murine colonic inflammation via a macrophage-dependent mechanism

“…When metallothionein-2 was inhibited in the parent MSCs, the antiinflammatory effects of MSC-Exos on macrophages in vitro were significantly suppressed. NF-κB signaling is a downstream target of metallothionein-2 (27,43). Consistent with this, MSC-Exos induced a significant decrease in NF-κB activity, whereas this effect was compromised when the expression of metallothionein-2 in MSC-Exos was inhibited.…”

“…As expected, the inhibitory effect of MSC-Exos on NF-κB activation was compromised as well ( Figure 8E). It has been reported that metallothionein-2 could enhance IκBα transcription via interacting with myeloid zinc finger 1 (MZF1), which directly bound to IκBα promoter (27). In agreement with this, MSC-Exos failed to enhance IκBα transcription in macrophages when MZF1 was knocked down using siRNA (Supplemental Figure 6E), implying a vital role of MZF1 on the increase of IκBα transcription.…”

“…As expected, the reduction of metallothionein-2 in MSC-Exos interfered with the antiinflammatory effects of MSC-Exos both in vitro ( Figure 8D) and in vivo (Supplemental Figure 6, A-C). A previous study revealed that metallothionein-2 could attenuate NF-κB activity (27). Indeed, treatment with MSC-Exos dose-dependently resulted in reduced level of phosphorylated IκBα in macrophages but increased total IκBα level in both protein and mRNA ( Figure 8E and Supplemental Figure 6D).…”

MZF1 and SCAND1 Reciprocally Regulate CDC37 Gene Expression in Prostate Cancer

“…Besides, MZF1 might play key roles also in tumor microenvironment such as mesenchymal stem cell differentiation into cancer-associated fibroblasts [20]. However, MZF1 has also been shown to activate tumor suppressor genes such as FPN [41], NFKBIA [42], and SMAD4 [43]. In a more complex manner, MZF1 also plays a transcriptional repressor role for pro-tumorigenic genes such as MMP-2 [44] and IGF-IR [45].…”

Molecular Bases of Mechanisms Accounting for Drug Resistance in Gastric Adenocarcinoma

“…Thus, the refractoriness to irinotecan and cisplatin may be due in part to MTs because (i) MTs have been found up-regulated in GAC, affecting the efficacy of cisplatin and irinotecan [51,52]; (ii) irinotecan induces MTs up-regulation promoting the development of chemoresistance in GAC patients [51]; (iii) the combination of MTs overexpression and p27 down-regulation seems to be related with poor prognosis of GAC patients [56]. In contrast, another study reported that GAC with a higher MT2A expression showed a better response to chemotherapy and prolonged survival [57,58]. Moreover, some studies revealed lower MTs expression in GAC than in the surrounding healthy tissue [59].…”