Transglutaminase 2 enhances hepatocyte growth factor signaling to drive the mesothelioma cancer cell phenotype.
Transglutaminase 2 enhances hepatocyte growth factor signaling to drive the mesothelioma cancer cell phenotype.
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DOI：
10.1002/mc.23399
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发表时间：
2022-06
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
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作者：
转氨酶2（TG 2）是一种重要的间皮瘤癌细胞存活蛋白。然而，TG 2维持间皮瘤细胞存活的机制尚不清楚。我们目前的研究表明，TG 2驱动肝细胞生长因子（HGF）依赖性MET受体信号传导，以维持侵袭性间皮瘤癌症表型。TG 2增加HGF和MET mRNA和蛋白水平以增强MET信号传导。TG 2失活降低MET酪氨酸激酶活性以减少癌细胞球状体形成、侵袭和迁移。我们还证实，HGF/MET信号转导是TG 2作用的生物学重要介质。使用遗传方法或MET抑制剂治疗降低MET水平可减少球状体形成、侵袭和迁移，这与MEK 1/2和ERK 1/2减少有关。此外，MEK 1/2和ERK 1/2抑制剂抑制癌症表型。此外，MET敲除间皮瘤细胞形成的肿瘤比野生型细胞小10倍，并且这些肿瘤显示出MET、MEK 1/2和ERK 1/2活性降低。这些发现表明，TG 2在培养的间皮瘤细胞和肿瘤中维持HGF和MET水平，以驱动HGF/MET、MEK 1/2和ERK 1/2信号传导，从而维持侵袭性间皮瘤癌症表型。
Transglutaminase 2 (TG2) is an important mesothelioma cancer cell survival protein. However, the mechanism whereby TG2 maintains mesothelioma cell survival is not well understood. We present studies showing that TG2 drives hepatocyte growth factor (HGF)-dependent MET receptor signaling to maintain the aggressive mesothelioma cancer phenotype. TG2 increases HGF and MET mRNA and protein levels to enhance MET signaling. TG2 inactivation reduces MET tyrosine kinase activity to reduce cancer cell spheroid formation, invasion and migration. We also confirm that HGF/MET signaling is a biologically important mediator of TG2 action. Reducing MET level using genetic methods or treatment with MET inhibitors reduces spheroid formation, invasion and migration and this is associated with reduced MEK1/2 and ERK1/2. In addition, MEK1/2 and ERK1/2 inhibitors suppress the cancer phenotype. Moreover, MET knockout mesothelioma cells form 10-fold smaller tumors compared to wild-type cells and these tumors display reduced MET, MEK1/2 and ERK1/2 activity. These findings suggest that TG2 maintains HGF and MET levels in cultured mesothelioma cells and tumors to drive HGF/MET, MEK1/2 and ERK1/2 signaling to maintain the aggressive mesothelioma cancer phenotype.
影响因子：
8.8
作者：
Harvey, P;Warn, A;Dobbin, S;Arakaki, N;Daikuhara, Y;Jaurand, M C;Warn, R M
通讯作者：
Warn, R M