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

作者：Shan Zhang, Hong‐Fei Yao, Hui Li, Tong Su, Shu-Heng Jiang, Hao Wang, Zhigang Zhang, Fangyuan Dong, Qin Yang, Xiaomei Yang · 发表于：Cellular Oncology · 年份：2023 · DOI：10.1007/s13402-023-00824-7 · 被引用次数：30 · 研究领域：Blood properties and coagulation、Rheology and Fluid Dynamics Studies、Adipokines, Inflammation, and Metabolic Diseases

Transglutaminases (TGs) are multifunctional enzymes exhibiting transglutaminase crosslinking, as well as atypical GTPase/ATPase and kinase activities. Here, we used an integrated comprehensive analysis to assess the genomic, transcriptomic and immunological landscapes of TGs across cancers. Gene expression and immune cell infiltration patterns across cancers were obtained from The Cancer Genome Atlas (TCGA) database and Gene Set Enrichment Analysis (GSEA) datasets. Western blotting, immunofluorescence staining, enzyme-linked immunosorbent assays, and orthotopic xenograft models were used to validate our database-derived results. We found that the overall expression of TGs (designated as the TG score) is significantly upregulated in multiple cancers and related to a worse patient survival. The expression of TG family members can be regulated through multiple mechanisms at the genetic, epigenetic and transcriptional levels. The expression of transcription factors crucial for epithelial-to-mesenchymal transition (EMT) is commonly correlated with the TG score in many cancer types. Importantly, TGM2 expression displays a close connection with chemoresistance to a wide range of chemotherapeutic drugs. We found that TGM2 expression, F13A1 expression and the overall TG score were positively correlated with the infiltration of immune cells in all cancer types tested. Functional and clinical verification revealed that a higher TGM2 expression is linked with a worse patient survival, an...