Transglutaminases are oncogenic biomarkers in human cancers and therapeutic targeting of TGM2 blocks chemoresistance and macrophage infiltration in pancreatic cancer

Abstract

Backgroud: Transglutaminases (TGs) are multifunctional enzymes with transglutaminase cross-linking, atypical GTPase/ATPase and kinase activity. Here, an integrated comprehensive analysis shows the genomic, transcriptomic and immunological landscapes of the TGs varies among different cancers. Methods Gene expression pattern and immune cell infiltration in pan-cancer were obtained from The Cancer Genome Atlas (TCGA) databases and Gene Set Enrichment Analysis (GSEA) datasets. Western blotting, immunofluorescence, ELISA, and orthotopic xenograft model were performed to validate our database-derived results. Results The overall expression of TGs (designated as TG score) is significantly upregulated in multiple cancers and related to worse patient survial. The expression of the TG family can be regulated by multiple mechanisms at the genetic, epigenetic and transcriptional levels. Transcriptionfactors crucial for epithelial to mesenchymal transition (EMT) are commonly correlated with TG score in many cancer types. Importantly, TGM2 expression displays a close connection with the chemoresistances of a wide range of chemodrugs. TGM2, F13A1 and overall TG score are positively correlated with the infiltration of immune cells in all cancer types tested. Functional and clinical verification reveals that higher TGM2 expression is linked with worse patient survival, increased IC50 value of gemcitabine, and abundant tumor-infiltrating macrophages in pancreatic cancer. Mechanistically, increased C-C motif chemokine ligand 2 (CCL2) release affored by TGM2 contributes to macrophage infiltration with tumor microenvironment. Conclusions These results reveal the relevances and molecular networks of TG genes in human cancers, highlighting the significance of TGM2 in pancreatic cancer which may provide some promising directions for immunotherapy and dealing with chemoresistance.

Pancreatic Cancer-Secreted Proteins: Targeting Their Functions in Tumor Microenvironment

“…This activity plays a role in regulating oxidative stress, thus negatively affecting proliferation and upregulating apoptosis in PDAC cells, as demonstrated by knockdown experiments [63]. The transglutaminase-2 gene (TGM2) has also been identified as an important extracellular cross-linking enzyme involved in ECM turnover, and its levels were associated with poor survival in pancreatic cancer patients [64]. Annexins dysregulation has also been reported as a common feature in several cancers [65], and, among them, soluble ANXA5 (Annexin A5) has been described for its activity in cell membrane resealing [66], an essential repair machinery that promotes survival in invasive cancer cells [67].…”