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

Abstract

BackgroundMetallothionein 2A (MT2A) as a stress protein, plays a protective role in gastric mucosal barrier. Its role in the development of gastric cancer (GC) is unclear. The mechanism of MT2A will be investigated in gastric tumorigenesis.MethodsMT2A expression was detected in 973 gastric specimens. The biological function was determined through ectopic expressing MT2A in vitro and in vivo. The possible downstream effectors of MT2A were investigated in NF-κB signaling. The protein levels of MT2A, IκB-α and p-IκB-α (ser32/36) expression were analyzed in a subset of 258 patients by IHC staining. The prognostic effects of MT2A, status of IκB-α and TNM stage were evaluated using the Kaplan-Meier method and compared using the log-rank test.ResultsDecreased MT2A expression was detected in cell lines and primary tumors of GC. In clinical data, loss of MT2A (MT2A + in Normal (n =171, 76.0%); Intestinal metaplasia (n = 118, 50.8%); GC (n = 684. 22.4%, P < 0.001)) was associated with poor prognosis (P < 0.001), advanced TNM stage (P = 0.05), and down-regulation of IκB-α expression (P < 0.001). Furthermore, MT2A was the independent prognostic signature segregated from the status of IκB-α and pathological features. In addition, MT2A inhibited cell growth through apoptosis and G2/M arrest, which negatively regulated NF-κB pathway through up-regulation of IκB-α and down-regulation of p-IκB-α and cyclin D1 expression.ConclusionsMT2A might play a tumor suppressive activity through inhibiting NF-κB signaling and may be a prognostic biomarker and potential target for individual therapy of GC patients.

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

“…Takano and colleagues demonstrated that transgenic mice with metallothionein overexpression were more resistant to neutrophilic lung inflammation and lung edema induced by intratracheal challenge with LPS (52). Metallothionein-2 has also been found to be a critical regulator of NF-κB signaling because its upregulation attenuates NF-κB activity in tumor cells, keloid fibroblastic cells, as well as cardiomyocyte cells (53)(54)(55)(56). In line with these studies, our results demonstrated the antiinflammatory effects of metallothionein-2 on both macrophages and mouse colitis models.…”

Epigenetic silencing of DACH1 induces the invasion and metastasis of gastric cancer by activating TGF‐β signalling

“…The information of these cells was published in our previous articles [20,21]. Cells were passaged 1:3 once 80% confluence (∼10 6 cells) was reached on a 75 cm 2 culture flask (NEST Biotechnology, Jiangsu, China).…”

“…Seven gastric cell lines (AGS, BGC823, SGC-7901, NCI-N87, NUGC3, MGC803 and MKN45) and one immortalized human gastric mucosal cell line GES-1 were previously established and maintained in DMEM medium (Invitrogen, Carlsbad, CA, USA) supplemented with 10% foetal bovine serum (FBS). The information of these cells was published in our previous articles [20,21]. Cells were passaged 1:3 once 80% confluence (~10 6 cells) was reached on a 75 cm 2 culture flask (NEST Biotechnology, Jiangsu, China).…”

Effect of Inulin on Proteome Changes Induced by Pathogenic Lipopolysaccharide in Human Colon

“…Our findings are in agreement with those of Inoue et al [35] who demonstrated the anti-inflammatory effects of metallothioneins on disturbances of lung, kidney and liver induced by LPS. Moreover, metallothioneins are known to inhibit the NF- k B signaling [36] and to be downregulated in the intestinal mucosa of patients with inflammatory bowel disease and in gastrointestinal tumors [37, 38]. …”