Hippo transducer TAZ promotes epithelial mesenchymal transition and supports pancreatic cancer progression

Abstract

Transcriptional co-activator with PDZ binding motif (TAZ) is a transducer of the Hippo pathway and promotes cancer development and progression. In the present study, we sought to determine the roles and underlying mechanisms of elevated expression and activation of TAZ in pancreatic cancer development and progression. The mechanistic role of TAZ and Hippo signaling in promotion of pancreatic cancer development and progression was examined using cell culture, molecular biology, and mouse models. The relevance of our experimental and mechanistic findings was validated using human pancreatic tumor specimens. We found that TAZ expression was markedly higher in pancreatic tumors than in normal pancreatic tissue. Further analysis of the correlation of TAZ expression with tissue microarray clinicopathologic parameters revealed that this expression was positively associated with tumor differentiation. Also, TAZ expression was higher in pancreatic cancer cell lines than in pancreatic ductal epithelial cells. TAZ activation in pancreatic cancer cells promoted their proliferation, migration, invasion, and epithelial-mesenchymal transition. Further mechanistic studies demonstrated that aberrant expression and activation of TAZ in pancreatic cancer cells resulted from suppression of the expression of Merlin, a positive regulator upstream of the Hippo pathway, and that the oncogenic function of TAZ in pancreatic cancer cells was mediated by TEA/ATTS domain transcription factors. Therefore, TAZ functioned as an oncogene and promoted pancreatic cancer epithelial-mesenchymal transition and progression. TAZ thus may be a target for effective therapeutic strategies for pancreatic cancer.

Activated hippo signal pathway inhibits cell proliferation and promotes apoptosis in NK/T cell lymphoma cells

“…As reported, YAP was significantly up‐regulated in many tumors such as lung, oesophagus, bladder, and cervix (reviewed in Segrelles et al). During the oncogenesis of pancreatic cancer, YAP mediated epithelial‐mesenchymal transition (EMT) and cancer cell proliferation . Additionally, MST1/2 deficiency resulted in cell overgrowth and hepatocellular carcinoma (HCC), and overexpression of MST1 and MST2 could suppress HCC development through inactivation of the YAP oncogene .…”

“…During the oncogenesis of pancreatic cancer, YAP mediated epithelial-mesenchymal transition (EMT) and cancer cell proliferation. 40 Additionally, MST1/2 deficiency resulted in cell overgrowth and hepatocellular carcinoma (HCC), and overexpression of MST1 and MST2 could suppress HCC development through inactivation of the YAP oncogene. 41 The absence of Sav1 or MST1/2 may lead to bigger liver, causing the formation of tumors.…”

Insulin Receptor and GPCR Crosstalk Stimulates YAP via PI3K and PKD in Pancreatic Cancer Cells

“…These studies indicate that Yap acts downstream of K-Ras and that its hyper-activation can compensate for the need of K-Ras mutant expression in PDAC (42). Several studies indicate that YAP and TAZ are active in PDAC patient tumor samples (26–28). However, the impact of crosstalk between insulin/IGF-1R and GPCR signaling pathways on YAP/TAZ activity had not been previously examined in PDAC cells or in any other cell type.…”

“…The YAP/TAZ pathway, originally identified in Drosophila , is attracting intense attention as a key regulator of development, organ-size, tissue regeneration and tumorigenesis. It is increasingly accepted that YAP/TAZ acts as a context-specific oncogene and several studies indicate that YAP and TAZ are overactive in PDAC patient tumor samples (26–28). Here, we examined the impact of crosstalk between the insulin receptor and GPCR signaling pathways on the regulation of YAP localization, phosphorylation and transcriptional activity in PDAC cells.…”

Epigenetics of epithelial‐to‐mesenchymal transition in pancreatic carcinoma

“…EMT in PDAC is regulated and activated by other pathways as well, among them hippo, NFkB/hypoxia, and Notch‐1 . This complexity shows that EMT is a strictly regulated mechanism of outstanding importance for PDAC cells.…”