Tissue transglutaminase-2 promotes gastric cancer progression via the ERK1/2 pathway

Abstract

Gastric cancer (GC) is one of the most common tumors worldwide and involves extensive local tumor invasion, metastasis, and poor prognosis. Understanding mechanisms regulating progression of GC is necessary for developing effective therapeutic strategies. Tissue transglutaminase-2 (TG2), a multifunctional member of the transglutaminase family, has been shown to be critical for tumor initiation and progression. However, how TG2 promotes the progression of GC is unknown. We report that TG2 was highly expressed in GC tissues and positively associated with depth of tumor invasion and late TNM stage. With gain- and loss-of-function approaches, we observed that TG2 promoted GC cell proliferation, migration, invasion, as well as tumorigenesis and peritoneal metastasis in vivo. These events were associated with the ERK1/2 pathway activation and an ERK1/2 inhibitor (U0126) inhibited cell proliferation, migration, and invasion induced by overexpression of TG2. In summary, TG2 contributes to tumorigenesis and progression of GC by activating the ERK1/2 signaling pathway and is a potential therapeutic target of metastatic gastric cancer.

Transglutaminase 2 takes center stage as a cancer cell survival factor and therapy target

“…TG2 levels are increased in cancer cells and tissues in leukemia, breast cancer, ovarian cancer, prostate cancer, lung cancer, glioblastoma, renal cancer, epidermal squamous cell carcinoma, pancreatic cancer, cervical cancer, esophageal adenocarcinoma, oral squamous cell carcinoma, mesothelioma, gastric cancer, and colon cancer . Moreover, TG2 levels are further enriched in cancer stem cells where it functions to maintain the cancer stem cell phenotype .…”

“…TG2 is highly expressed in human gastric tumors and expression is positively correlated with tumor stage . TG2 promotes gastric cancer cell proliferation, migration, invasion, tumor formation, and peritoneal metastasis via a mechanism that requires ERK1/2 activity (Figure A). In addition, GX1, a cyclic 7‐mer peptide that inhibits gastric cancer by suppressing neovascularization, binds to TG2 in tumor‐associated vascular endothelial cells, to reduce TG2 GTP binding activity and suppresses NF‐κB and HIF‐1α signaling.…”

“…“TG2‐GTP” indicates that the GTP binding domain has been strongly implicated in mediating the regulation. A, The gastric cancer references are . B, The breast cancer references are …”

Letter: the coeliac stomach – a significant increase in tissue transglutaminase antibodies is associated with gastritis

“…Although no difference in the severity of villous atrophy between the groups was found (possibly due to information biases), which differs from other reports of severe villous atrophy in association with gastritis, 1,5,6 we feel that the increase in tTG antibodies observed in the gastritis group might indicate either a longer disease duration in these individuals or perhaps a role of the gastric mucosa in the gluten-mediated immune reaction, knowing that tTG is ubiquitous and active in gastric mucosal cells in several diseases. 7,8 SIRS, In 2016 several studies published in Alimentary Pharmacology & Therapeutics focussing on the role of hepatitis B surface antigen (HBsAg) seroclearance and risk of hepatocellular carcinoma (HCC) were published. [1][2][3][4] We read with great interest these articles, especially the one entitled 'Nested case-control study: hepatocellular carcinoma risk after hepatitis B surface antigen seroclearance' by Gounder et al 1 Although effective vaccines for hepatitis B virus have been available for more than two decades, chronic hepaitits B (CHB) virus infection remains a leading cause of severe liver cirrhosis and HCC worldwide.…”

“…Although no difference in the severity of villous atrophy between the groups was found (possibly due to information biases), which differs from other reports of severe villous atrophy in association with gastritis, 1,5,6 we feel that the increase in tTG antibodies observed in the gastritis group might indicate either a longer disease duration in these individuals or perhaps a role of the gastric mucosa in the gluten-mediated immune reaction, knowing that tTG is ubiquitous and active in gastric mucosal cells in several diseases. 7,8…”