Amplification of transglutaminase 2 enhances tumor-promoting inflammation in gastric cancers

Abstract

Tumor-promoting inflammation is a hallmark of cancer and is highly associated with tumor progression, angiogenesis, and metastasis. Tumor-associated macrophages (TAMs) are major drivers of tumor-promoting inflammation, but due to the complexity of the tumor microenvironment, the detailed regulatory mechanisms are still under investigation. Here, we investigated a novel role for transglutaminase 2 (TGM2) in the development of tumor-promoting inflammation and recruitment of TAMs to gastric cancer (GC) tissues. When estimated by array comparative genomic hybridization and droplet digital PCR, the copy numbers of the TGM2 gene were amplified in 13.6% (14/103) of GC patients and positively associated with TGM2 expression. Gene set enrichment analysis of expression microarray data for GC samples with high or low TGM2 expression showed that increased TGM2 expression was associated with tumor-promoting inflammation in GC. In addition, the expression of TGM2 was correlated with the expression of markers for macrophages, neutrophils, blood vessels, and lymphatic vessels. Overexpression of TGM2 in GC cells augmented the IL-1β-induced secretion of macrophage-recruiting chemokines and NF-κB activation. TGM2 protein levels were associated with the expression levels of the macrophage marker CD163 in human GC tissue samples. Moreover, GC patients with high expression of TGM2 had a worse prognosis than those with low expression of TGM2. These results suggest TGM2 as a novel regulator of the tumor microenvironment of GC and provide a promising target for constraining tumor-promoting inflammation.

Prognostic and therapeutic implications of extracellular matrix associated gene signature in renal clear cell carcinoma

“…Its expression is associated with the chemoattraction of immune cells 24 TGM2 (Transglutaminase 2) 5 TGM2 assists in posttranslational modification of proteins. Its overexpression is involved in several cancers including pancreatic, prostate, ovarian and breast cancer 25 COL3A1 (Collagen Type III Alpha 1 Chain) 5 COL3A1 expresses components of fibrillar collagen which forms the skin and other tissues. Its over-expression in involved in multiple cancers 26 ANXA4 (Annexin A4) 4 Annexin A4 is calcium-regulated phospholipid-binding protein.…”

Meta-Analysis Reveals the Prognostic Relevance of Nuclear and Membrane-Associated Bile Acid Receptors in Gastric Cancer

“…IPA analysis of each common DCG list for predicted upstream regulators revealed that genes involved in lipid metabolism such as NR5A1 and PPARA were predicted to be active, whereas hallmark tumor-suppressor genes including BRCA1 and TP53 were predicted to be downregulated (Figure 5 c). By contrast, upstream regulators predicted to be active for membrane BARs were primarily oncogenes including transforming growth factor β 1 ( TGFβ1 ) ( 61 ), ETS-related gene ( ERG ) ( 62 ), transglutaminase 2 ( TGM2 ) ( 63 ), and TEA domain family member 1-4 ( TEAD1-4 ) ( 64 ), whereas regulators predicted to be inhibited were other oncogenes such as SAM pointed domain containing ETS transcription factor ( SPDEF ) ( 65 ), zinc finger protein 217 ( ZNF217 ) ( 66 ), and non-POU domain containing octamer binding ( NONO ) ( 62 ) (Figure 5 d). Of note, multiple genes promoting epithelial-mesenchymal transition ( EMT ) were predicted active with membrane BARs such as hypoxia-inducible factor 1-alpha ( HIF1A ), twist family BHLH transcription factor 1 ( TWIST1 ) and vascular endothelial growth factor A ( VEGFA ), whereas those opposing EMT, such as CDH1 ( 67 ), were predicted to be inhibited (see Supplementary Digital Content 4, http://links.lww.com/CTG/A489 ).…”

Proteomics Analysis of Gastric Cancer Patients with Diabetes Mellitus

“…In the ORA, we found two downregulated disease pathways, “Intestinal Disease” and “Epithelial Cancers”, in DM patients with GC, with 10.7 and 9.6 enrichment ratios, respectively. This result has particular relevance since the five shared proteins together with one protein specifically associated with each of the gene sets—seven in total ( Table 3 )—were already reported as being associated with GC and gastric pre-malignant lesions, as follows: (1) the down-regulation of claudin-3, a tight junction protein, was associated with GC progression [ 26 ]; (2) the polymeric immunoglobulin receptor protein, a major player of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins, was observed to be higher in gastric intestinal metaplasia compared to in normal tissues and cancer [ 27 ]; (3) cadherin-17, a transmembrane glycoprotein and member of the cadherin family with an important role in tumorigenesis, was found to be over-expressed in GC [ 28 ]; (4) villin-1, an actin-binding protein, was observed to be significantly lower in GC compared to non-neoplastic mucosa [ 29 ]; (5) GC patients whose tumors featured high expressions of Transglutaminase-2 (protein-glutamine gamma-glutamyltransferase 2), an acyltransferase enzyme that also serves as a G protein for several transmembrane receptors and acts as a co-receptor for integrin β1 and β3 integrins [ 30 ], were observed to have a worse prognosis than those with a low expression of this enzyme [ 31 ]; (6) mucin-13, a glycoprotein mainly expressed in the digestive tract, was found to be overexpressed in intestinal-type GC [ 32 ]; (7) desmoglein-2, a major component of the desmosomes, is a cell adhesion molecule with functional similarities to E-cadherin and was described to be abnormally expressed in GC [ 33 ]. Taken together, these seven downregulated proteins in DM patients form a panel of candidate targets to be addressed in future studies to better understand the interactions between these diseases.…”