PMID- 31849712 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240422 IS - 1664-042X (Print) IS - 1664-042X (Electronic) IS - 1664-042X (Linking) VI - 10 DP - 2019 TI - Yes-Associated Protein 1 Plays Major Roles in Pancreatic Stellate Cell Activation and Fibroinflammatory Responses. PG - 1467 LID - 10.3389/fphys.2019.01467 [doi] LID - 1467 AB - Background: Yes-associated protein 1 (YAP), a transcriptional co-activator and major effector of the Hippo pathway, regulates cell differentiation and morphology in many cell types and supports aberrant tumor growth. Recent studies showed that YAP is expressed in pancreas tissues in pancreatic ductal adenocarcinoma (PDAC) patients and experimental models of PDAC, with YAP largely found in cancer cells and pancreatic stellate cells (PaSC) in the stroma. Methods and Results: We studied here the role of YAP in the activated phenotype of PaSC. We found that YAP is expressed at low levels in normal mouse pancreas, but protein levels significantly increased after pancreas inflammatory damage induced by repeated cerulein administration in wild-type mice or upon initiation of neoplastic transformation of the pancreas parenchyma in Ptf1-Cre;LSL-Kras(G12D/+) (KC) mice. In these animal models, YAP upregulation occurred in parallel with activation and proliferation of PaSC. Consistent with these findings, we found robust YAP expression in culture-activated mouse and human PaSC but not in quiescent, freshly isolated cells. Fully activated PaSC isolated from KC mice or PDAC patient tissues exhibited robust nuclear YAP suggesting YAP transcriptional activity. Agents that induce quiescence such as the Bromodomain and Extra-Terminal (BET) inhibitor iBET151 and the p38 MAPK inhibitor SB203580 reduced YAP levels in PaSC. Stimulation of PaSC with the potent mitogen PDGF elicited marked YAP Ser127 phosphorylation. However, unexpectedly, this effect did not diminish YAP nuclear localization, suggesting that YAP phosphorylation at this site does not govern YAP cellular localization in PaSC. siRNA-mediated knockdown of YAP reduced PDGF-induced PaSC expansion in culture and blunted the persistent activation of Akt and ERK elicited by PDGF stimulation, supporting a role for YAP in PDGF-induced cell growth. YAP knockdown also blunted fibroinflammatory gene expression responses both in unstimulated and transforming growth factor beta 1 (TGFbeta1)-stimulated PaSC. Conclusion: Our data suggest a central role for YAP in sustaining the activated phenotype and fibroinflammatory responses in PaSC. Moreover, our findings indicate that a complex crosstalk between YAP, TGFbeta1, and PDGF pathways regulates PaSC activity and growth. CI - Copyright (c) 2019 Hu, Yang, Su, Waldron, Zhi, Li, Xia, Pandol and Lugea. FAU - Hu, Cheng AU - Hu C AD - Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China. AD - Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States. FAU - Yang, Jiayue AU - Yang J AD - Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States. AD - Department of Endocrinology, Zhongda Hospital Southeast University, Nanjing, China. FAU - Su, Hsin-Yuan AU - Su HY AD - Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States. FAU - Waldron, Richard T AU - Waldron RT AD - Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States. AD - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States. FAU - Zhi, Mengmeng AU - Zhi M AD - Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States. AD - Department of Endocrinology, Zhongda Hospital Southeast University, Nanjing, China. FAU - Li, Ling AU - Li L AD - Department of Endocrinology, Zhongda Hospital Southeast University, Nanjing, China. FAU - Xia, Qing AU - Xia Q AD - Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, China. FAU - Pandol, Stephen J AU - Pandol SJ AD - Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States. AD - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States. FAU - Lugea, Aurelia AU - Lugea A AD - Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States. AD - Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States. LA - eng GR - P01 CA163200/CA/NCI NIH HHS/United States GR - P01 DK098108/DK/NIDDK NIH HHS/United States GR - R01 AA019954/AA/NIAAA NIH HHS/United States GR - U24 DK098085/DK/NIDDK NIH HHS/United States PT - Journal Article DEP - 20191203 PL - Switzerland TA - Front Physiol JT - Frontiers in physiology JID - 101549006 PMC - PMC6901825 OTO - NOTNLM OT - fibrosis OT - pancreatic cancer OT - pancreatic stellate cells OT - pancreatitis OT - yes-associated protein 1 EDAT- 2019/12/19 06:00 MHDA- 2019/12/19 06:01 PMCR- 2019/12/03 CRDT- 2019/12/19 06:00 PHST- 2019/08/31 00:00 [received] PHST- 2019/11/14 00:00 [accepted] PHST- 2019/12/19 06:00 [entrez] PHST- 2019/12/19 06:00 [pubmed] PHST- 2019/12/19 06:01 [medline] PHST- 2019/12/03 00:00 [pmc-release] AID - 10.3389/fphys.2019.01467 [doi] PST - epublish SO - Front Physiol. 2019 Dec 3;10:1467. doi: 10.3389/fphys.2019.01467. eCollection 2019.