Abstract
BackgroundHippo/YAP pathway is known to be important for development, growth and organogenesis, and dysregulation of this pathway leads to tumor progression. We and others find that YAP is up-regulated in pancreatic ductal adenocarcinoma (PDAC) and associated with worse prognosis of patients. Activated pancreatic stellate cells (PSCs) forming the components of microenvironment that enhance pancreatic cancer cells (PCs) invasiveness and malignance. However, the role and mechanism of YAP in PDAC tumor-stromal interaction is largely unknown.MethodsThe expression of YAP in Pancreatic cancer cell lines and PDAC samples was examined by Western blot and IHC. The biological role of YAP on cancer cell proliferation, epithelial-mesenchymal transition (EMT) and invasion were evaluated by MTT, Quantitative real-time PCR analysis, Western blot analysis and invasion assay. The effect of YAP on PSC activation was evaluated by PC-PSC co-culture conditions and xenograft PDAC mouse model.ResultsFirstly, knockdown of YAP inhibits PDAC cell proliferation and invasion in vitro. In addition, YAP modulates the PC and PSC interaction via reducing the production of connective tissue growth factor (CTGF) from PCs, inhibits paracrine-mediated PSC activation under PC-PSC co-culture conditions and in turn disrupts TGF-β1-mediated tumor-stromal interactions. Lastly, inhibiting YAP expression prevents tumor growth and suppresses desmoplastic reaction in vivo.ConclusionsThese results demonstrate that YAP contributes to the proliferation and invasion of PC and the activation of PSC via tumor-stromal interactions and that targeting YAP may be a promising therapeutic strategy for PDAC treatment.
Highlights
Hippo/YES-associated protein (YAP) pathway is known to be important for development, growth and organogenesis, and dysregulation of this pathway leads to tumor progression
pancreatic stellate cells (PSC) are activated by direct contact with pancreatic cancer cells (PCs) or paracrine cytokines produced by PCs, including sonic Hedgehog (SHH), connective tissue growth factor (CTGF), TGF- β1, and fibroblast growth factor (FGF) [4, 6]
YAP is overexpressed in pancreatic cancer tissues To determine whether YAP is overexpressed at the protein level in human pancreatic ductal adenocarcinoma (PDAC) tissues, we examined YAP expression in five human pancreatic cancer tissues and the corresponding normal pancreatic tissue via western blot
Summary
Hippo/YAP pathway is known to be important for development, growth and organogenesis, and dysregulation of this pathway leads to tumor progression. We and others find that YAP is up-regulated in pancreatic ductal adenocarcinoma (PDAC) and associated with worse prognosis of patients. The role and mechanism of YAP in PDAC tumor-stromal interaction is largely unknown. Pancreatic cancer is a highly invasive and metastatic cancer, PSCs are the major cellular contributors to the desmoplastic reaction in PDAC and are thought to play an important role in the pathobiology of pancreatitis and pancreatic cancer [4]. The detailed molecular mechanisms underlying the activation of PSCs in pancreatic cancer and the desmoplastic reaction induction of tumor cell proliferation are still unclear. Understanding the molecular mechanisms that control tumor growth and the desmoplastic reaction in PDAC is important
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