Gpx3 prevents migration and invasion in gastric cancer by targeting NFкB/Wnt5a/JNK signaling. Cai Meijuan,Sikong Yinhe,Wang Qing,Zhu Shuzhen,Pang Fei,Cui Xiangdan International journal of clinical and experimental pathology PURPOSE:Metastasis is the hallmark of gastric cancer (GC) and is the most widely recognized reason for GC-related deaths. However, the underlying mechanism of GC metastasis remains unknown. Herein we sought to investigate the biologic function of Gpx3 in gastric tumor metastasis and the underlying mechanism. METHODS:Cell migration and invasion was determined with Transwell chamber assay. Western blotting was used to determine protein expression levels of Gpx3, EMT markers and Wnt signaling related molecules. metastasis was determined with experiment lung metastasis model in tumor xenografts. RESULTS:Gpx3 expression was lower in GC patients and GC cell lines when compared with normal tissues and cells. Further studies showed that overexpression of Gpx3 was able to inhibit GC cell migration and invasion whereas Gpx3 knockdown promoted cell migration and invasion. Furthermore, AGS cells overexpressing Gpx3 showed lower metastatic potential when compared with the parental cells. Gpx3 was also found to regulate the expression of EMT markers. Mechanistic study showed that Gpx3 selectively inhibited Wnt/JNK signaling pathway over canonical Wnt/β-catenin pathway. The data revealed that blockade of NFкB and JNK signaling pathway abolished siGpx3-induced cell migration and invasion. CONCLUSIONS:Taken together, we identify Gpx3 as a suppressor of GC metastasis. Above results provide the rationale that regulation of Gpx3 serves as a potential therapeutic option for GC.

Analysis of Epithelial-Mesenchymal Transition Metabolism Identifies Possible Cancer Biomarkers Useful in Diverse Genetic Backgrounds. Matadamas-Guzman Meztli,Zazueta Cecilia,Rojas Emilio,Resendis-Antonio Osbaldo Frontiers in oncology Epithelial-to-mesenchymal transition (EMT) relates to many molecular and cellular alterations that occur when epithelial cells undergo a switch in differentiation generating mesenchymal-like cells with newly acquired migratory and invasive properties. In cancer cells, EMT leads to drug resistance and metastasis. Moreover, differences in genetic backgrounds, even between patients with the same type of cancer, also determine resistance to some treatments. Metabolic rewiring is essential to induce EMT, hence it is important to identify key metabolic elements for this process, which can be later used to treat cancer cells with different genetic backgrounds. Here we used a mathematical modeling approach to determine which are the metabolic reactions altered after induction of EMT, based on metabolomic and transcriptional data of three non-small cell lung cancer (NSCLC) cell lines. The model suggested that the most affected pathways were the Krebs cycle, amino acid metabolism, and glutathione metabolism. However, glutathione metabolism had many alterations either on the metabolic reactions or at the transcriptional level in the three cell lines. We identified Glutamate-cysteine ligase (GCL), a key enzyme of glutathione synthesis, as an important common feature that is dysregulated after EMT. Analyzing survival data of men with lung cancer, we observed that patients with mutations in GCL catalytic subunit (GCLC) or Glutathione peroxidase 1 (GPX1) genes survived less time than people without mutations on these genes. Besides, patients with low expression of ANPEP, GPX3 and GLS genes also survived less time than those with high expression. Hence, we propose that glutathione metabolism and glutathione itself could be good targets to delay or potentially prevent EMT induction in NSCLC cell lines. 10.3389/fonc.2020.01309