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

Sung-Yup Cho
Yumi Oh
Eui Man Jeong
Sanghui Park
Dakeun Lee
Xiaorui Wang
Qiqi Zeng
Hongyu Qin
Fang Hu
Hui Gong
Xi Liu
Guanjun Zhang
Deukchae Na
Jieun Lee
Jeesoo Chae
Yun-Suhk Suh
Seong-Ho Kong
Hyuk-Joon Lee
Jong-Il Kim
Hansoo Park
Chengsheng Zhang
Han-Kwang Yang
Charles Lee, The Jackson Laboratory

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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.