Distinctive expression and function of four GSDM family genes (GSDMA‐D) in normal and malignant upper gastrointestinal epithelium

Abstract

Gasdermin (GSDM or GSDMA), expressed in the upper gastrointestinal tract but frequently silenced in gastric cancers (GCs), regulates apoptosis of the gastric epithelium. It has three human homologs, GSDMB, GSDMC, and GSDMD (GSDM family) and they are considered to be involved in the regulation of epithelial apoptosis but not yet known. We investigated the expression pattern of the family genes in the upper gastrointestinal epithelium and cancers. Reverse transcriptase-polymerase chain reaction revealed that, unlike GSDMA expressed in differentiated cells, GSDMB is expressed in proliferating cells and GSDMD in differentiating cells. GSDMC, meanwhile, is expressed in both differentiating and differentiated cells. Colony formation assay showed that GSDMB, closely related to GSDMA, has no cell-growth inhibition activity in gastric cancer cells, and that GSDMC and GSDMD, respectively, exhibit the activity with different strengths from that of GSDMA. Expression analyses of the four family genes in esophageal and GCs suggested that GSDMC and GSDMD as well as GSDMA are tumor suppressors and that GSDMB, which was amplified and overexpressed in some GCs, could be an oncogene. The results of the expression analysis and colony formation assay suggest that each family gene may have a distinct function in the upper gastrointestinal epithelium.

GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophil-mediated bronchial hyperresponsiveness

“…GSDMB is expressed as an oncogene product in stem cell-resident regions of normal epithelium [23]. ORMDL3 is the third member of a gene family that encodes transmembrane proteins that are anchored in the ER [24].…”

Loss of conserved Gsdma3 self-regulation causes autophagy and cell death

“…In mouse, there are three homologues in the A cluster [Gasdermin A1-3 (Gsdma1, 2, 3)], four homologues in the C cluster (Gsdmc1, 2, 3,4), one homologue in the D cluster (Gsdmd) and no counterpart of human GSDMB [8]. GSDMA, GSDMC and GSDMD are all reported to be cancer suppressors, but GSDMB is considered to be an oncogene [9][10][11][12].…”

Gene polymorphism linked to increased asthma and IBD risk alters gasdermin-B structure, a sulfatide and phosphoinositide binding protein

“…The mouse genome contains three clusters of GSDM genes, encoding eight GSDMs (Gsdma1 to -3, Gsdmc1 to -4, and Gsdmd), but lacks the analog of the human GSDMB (also known as GSDML or PRO2521) (1). Based on the differential protein expressions in gastric and esophageal cancers, human GSDMA, GSDMC, and GSDMD are considered tumor suppressors whereas an overexpression of GSDMB in gastric, uterine cervix, and breast cancers was accompanied by tumor progression and metastasis (3)(4)(5)(6)(7)(8). The overexpression of GSDMC in metastatic melanoma cells is an exception to its apoptotic role (9).…”