Role of succinate dehydrogenase deficiency and oncometabolites in gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract.At the molecular level,GISTs can be categorized into two groups based on the causative oncogenic mutations.Approximately 85%of GISTs are caused by gain-of-function mutations in the tyrosine kinase receptor KIT or platelet-derived growth factor receptor alpha(PDGFRA).The remaining GISTs,referred to as wild-type(WT)GISTs,are often deficient in succinate dehydrogenase complex(SDH),a key metabolic enzyme complex in the tricarboxylic acid(TCA)cycle and electron transport chain.SDH deficiency leads to the accumulation of succinate,a metabolite produced by the TCA cycle.Succinate inhibitsα-ketoglutarate-dependent dioxygenase family enzymes,which comprise approximately 60 members and regulate key aspects of tumorigenesis such as DNA and histone demethylation,hypoxia responses,and m6A mRNA modification.For this reason,succinate and metabolites with similar structures,such as D-2-hydroxyglutarate and fumarate,are considered oncometabolites.In this article,we review recent advances in the understanding of how metabolic enzyme mutations and oncometabolites drive human cancer with an emphasis on SDH mutations and succinate in WT GISTs.

Interaction between cyclooxygenase-2,Snail,and E-cadherin in gastric cancer cells

AIM:To investigate the mechanisms of how cyclooxygenase-2(COX-2)regulates E-cadherin in gastric cancer cells.METHODS:COX-2 expression in human gastric cancer cell lines SGC-7901,BGC-823,MGC-803 and AGS were measured at the mRNA and protein level.COX-2 rich cell line SGC-7901 was chosen for subsequent experiments.siRNA mediated gene knockdown was used to investigate the impact of COX-2 on nuclear factor-κB (NF-κB),Snail,and E-cadherin in gastric cancer cells.Gene expression was determined by Western blot and real-time polymerase chain reaction.To analyze whether NF-κB inhibition could interrupt the modulatory effect of COX-2 or prostaglandin E2(PGE2)on E-cadherin,gastric cancer cells were treated with celecoxib or PGE2,in the presence of NF-κB specific siRNA.RESULTS:Highest expression level of COX-2 was found in SGC-7901 cells,both at mRNA and protein levels.siRNA mediated down-regulation of COX-2 led to a reduced expression of NF-κB and Snail,but an increased expression of E-cadherin in SGC-7901 cells.siRNA mediated down-regulation of NF-κB also led to a reduced expression of E-cadherin and Snail in SGC-7901 cells.However,COX-2 expression did not alter after cells were treated with NF-κB specific siRNA in SGC-7901 cells.Treatment of SGC-7901 cells with celecoxib led to a reduced expression of Snail but an increased expression of E-cadherin.In contrast,treatment of SGC-7901 cells with PGE2 led to an increased Snail and a decreased E-cadherin.However,siRNAmediated knockdown of NF-κB partially abolished the effect of celecoxib and PGE2 on the regulation of E-cadherin and Snail in SGC-7901 cells.CONCLUSION:COX-2 likely functions upstream of NF-κB and regulates the expression of E-cadherin via NF-κB/Snail signaling pathway in gastric cancer cells.

Acute esophageal obstruction caused by reverse migration of gastric bezoars: A case report

BACKGROUND Bezoars can be found anywhere in the gastrointestinal tract.Esophageal bezoars are rare.Esophageal bezoars are classified as either primary or secondary.It is rarely reported that secondary esophageal bezoars caused by reverse migration from the stomach lead to acute esophageal obstruction.Guidelines recommend urgent upper endoscopy(within 24 h)for these impactions without complete esophageal obstruction and emergency endoscopy(within 6 h)for those with complete esophageal obstruction.Gastroscopy is regarded as the mainstay for the diagnosis and treatment of esophageal bezoars.CASE SUMMARY A 59-year-old man was hospitalized due to nausea,vomiting and diarrhea for 2 d and sudden retrosternal pain and dysphagia for 10 h.He had a history of type 2 diabetes mellitus for 9 years.Computed tomography revealed dilated lower esophagus,thickening of the esophageal wall,a mass-like lesion with a flocculent high-density shadow and gas bubbles in the esophageal lumen.On gastroscopy,immovable brown bezoars were found in the lower esophagus,which led to esophageal obstruction.Endoscopic fragmentation was successful,and there were no complications.The symptoms of retrosternal pain and dysphagia disappeared after treatment.Mucosal superficial ulcers were observed in the lower esophagus.Multiple biopsy specimens from the lower esophagus revealed nonspecific findings.The patient remained asymptomatic,and follow-up gastroscopy 1 wk after endoscopic fragmentation showed no evidence of bezoars in the esophagus or the stomach.CONCLUSION Acute esophageal obstruction caused by bezoars reversed migration from the stomach is rare.Endoscopic fragmentation is safe,effective and minimally invasive and should be considered as the first-line therapeutic modality.