Yes-associated Protein Signaling Pathway Research Articles

RETRACTED: Cu(II) and Co(II) coordination polymers: Magnetic properties, regulating the YAP signaling pathway activation and exerting anticancer activity against breast cancer combined with Sevoflurane

• Two transition metal coordination polymers (CPs) have been prepared. • The two compounds possess antiferromagnetic coupling between neighboring metallic ions. • The two compounds against the breast cancer was determined and the detailed mechanism was investigated. Two transition metal coordination polymers (CPs) have been prepared via the corresponding metal salts reacting with flexible tripodal 1,3,5-tris(4-carbonylphenyloxy)benzene (H 3 TCPB) ligand under the conditions of solvothermal in the existence of auxiliary connector 4,4′-bis(imidazol-1-yl)biphenyl (bibp) or 1,4-bis(imidazol-1-yl)benzene (bib), and their chemical formula are {[Cu 3 (TCPB) 2 (bibp) 2 (dioxane) 2.5 (H 2 O) 2 ]·(DMF)} n ( 1 ) and [Co 1.5 (TCPB)(bib) 0.5 (DMF)] n ( 2 ). The magnetic investigations indicate that two compounds possess antiferromagnetic coupling between neighboring metallic ions. Their anti-cancer activities were evaluated and the related detailed mechanism was investigated. First of all, the inhibitory activity of the compounds on the breast cancer cells’ migration was assessed with trans -well method. Next, the Yes-associated protein (YAP) relative expression level in the cancer cells after compounds treatment was evaluated with real time reverse transcription-polymerase chain reaction (RT-PCR).

Trophoblast Stem-Cell-Derived Exosomes Improve Doxorubicin-Induced Dilated Cardiomyopathy by Modulating the let-7i/YAP Pathway

Trophoblast stem cells (TSCs) have been confirmed to play a cardioprotective role in heart failure. However, whether TSC-derived exosomes (TSC-exos) can protect against cardiac injury remains unclear. In the present study, TSC-exos were isolated from the supernatant of TSCs using the ultracentrifugation method and characterized by transmission electron microscopy and western blotting. Utilizing the public Gene Expression Omnibus (GEO) database, we found that let-7i and Yes-associated protein 1 (YAP) could participate in the development of heart failure. In vitro, AC16 cardiomyocytes subjected to doxorubicin (DOX) were treated with TSC-exos or let-7i mimic. Flow cytometry showed that TSC-exos and let-7i both decreased cardiomyocyte apoptosis. In vivo, mice that were intraperitoneally injected into DOX received either PBS, TSC-exos, or AAV9-let7iup for let-7i overexpression. Mice receiving TSC-exos and AAV9-let7iup showed improved cardiac function and decreased inflammatory responses, accompanied by downregulated YAP signaling. Mechanistically, TSC-exos could transfer let-7i to cardiomyocytes and silence the YAP signaling pathway. In conclusion, TSC-exos could alleviate DOX-induced cardiac injury via the let-7i/YAP pathway, which sheds new light on the application of TSC-exos as a potential therapeutic tool for heart failure.

The Histone Methyltransferase G9a Promotes Cholangiocarcinogenesis Through Regulation of the Hippo Pathway Kinase LATS2 and YAP Signaling Pathway.

Cholangiocarcinoma (CCA) is a highly malignant epithelial tumor of the biliary tree with poor prognosis. In the current study, we present evidence that the histone-lysine methyltransferase G9a is up-regulated in human CCA and that G9a enhances CCA cell growth and invasiveness through regulation of the Hippo pathway kinase large tumor suppressor 2 (LATS2) and yes-associated protein (YAP) signaling pathway. Kaplan-Meier survival analysis revealed that high G9a expression is associated with poor prognosis of CCA patients. In experimental systems, depletion of G9a by small interfering RNA/short hairpin RNA or inhibition of G9a by specific pharmacological inhibitors (UNC0642 and UNC0631) significantly inhibited human CCA cell growth in vitro and in severe combined immunodeficient mice. Increased G9a expression was also observed in mouse CCA induced by hydrodynamic tail vein injection of notch intracellular domain (NICD) and myr-Akt. Administration of the G9a inhibitor UNC0642 to NICD/Akt-injected mice reduced the growth of CCA, in vivo. These findings suggest that G9a inhibition may represent an effective therapeutic strategy for the treatment of CCA. Mechanistically, our data show that G9a-derived dimethylated H3K9 (H3K9me2) silenced the expression of the Hippo pathway kinase LATS2, and this effect led to subsequent activation of oncogenic YAP. Consequently, G9a depletion or inhibition reduced the level of H3K9me2 and restored the expression of LATS2 leading to YAP inhibition. Our findings provide evidence for an important role of G9a in cholangiocarcinogenesis through regulation of LATS2-YAP signaling and suggest that this pathway may represent a potential therapeutic target for CCA treatment.

Physalin D attenuates hepatic stellate cell activation and liver fibrosis by blocking TGF-β/Smad and YAP signaling

BackgroundHepatic fibrosis is considered integral to the progression of chronic liver diseases, as it leads to the development of cirrhosis and hepatocellular carcinoma. The activation of hepatic stellate cells (HSCs) is the dominant event in hepatic fibrogenesis. The transforming growth factor-β1 (TGF-β1) and Yes-associated protein (YAP) pathways play a pivotal role in HSC activation, hepatic fibrosis and cirrhosis progression. Therefore, targeting the TGF-β/Smad and YAP signaling pathways is a promising strategy for antifibrotic therapy. PurposeThe present study investigated the protective effects of Physalin D (PD), a withanolide isolated from Physalis species (Solanaceae), against liver fibrosis and further elucidated the mechanisms involved in vitro and in vivo. Study design/methodsWe conducted a series of experiments using carbon tetrachloride (CCl4)- and bile duct ligation (BDL)-induced fibrotic mice and cultured LX-2 cells. Serum markers of liver injury, and the morphology, histology and fibrosis of liver tissue were investigated. Western blot assays and quantitative real-time PCR were used to investigate the mechanisms underlying the antifibrotic effects of PD. ResultPD decreased TGF-β1-induced COL1A1 promoter activity. PD inhibited TGF-β1-induced expression of Collagen I and α-smooth muscle actin (α-SMA) in human hepatic stellate LX-2 cells. PD significantly ameliorated hepatic injury, including transaminase activities, histology, collagen deposition and α-SMA, in CCl4- or BDL-induced mice. Moreover, PD markedly decreased the expression of phosphorylated Smad2/3 in vitro and in vivo. Furthermore, PD significantly decreased YAP protein levels, and YAP knockdown did not further enhance the effects of PD, namely α-SMA inhibition, Collagen I expression and YAP target gene expression in LX-2 cells. ConclusionThese results clearly show that PD ameliorated experimental liver fibrosis by inhibiting the TGF-β/Smad and YAP signaling pathways, indicating that PD has the potential to effectively treat liver fibrosis.

Concentrated growth factor promotes gingival regeneration through the AKT/Wnt/β-catenin and YAP signaling pathways

Although concentrated growth factor (CGF) is known to promote gingival regeneration and improve the outcomes of clinical treatment, the mechanisms underlying its effects remain unknown. Therefore, this study aimed to elucidate the effects of CGF on gingival thickening. To this end, gingival mesenchymal stem cells (GMSCs) were treated with different concentrations of CGF, and the effects of CGF on cell proliferation and migration; collagen-1 (Col-1), fibronectin (FN), vascular endothelial growth factor (VEGF), and angiopoietin-1 (Ang-1) expression; and the AKT, Wnt/β-catenin, and Yes-associated protein (YAP) signalling pathways were investigated. The effects of CGF in vivo were also investigated in a rat buccal gingival injection model. GMSCs cultured with CGF showed improved cell proliferation and migration. Moreover, CGF treatment improved the levels of FN, Col-1, VEGF, and ANG-1. These effects of CGF were mediated by the AKT/Wnt and YAP pathways, with the AKT pathway possibly functioning upstream of the Wnt/β-catenin and YAP pathways. YAP was also shown to be overexpressed in the in vivo model. Thus, CGF can promote gingival regeneration, and YAP transport into the nucleus may be a key factor underlying this activity, which provides a novel perspective for gingival regeneration and further promotion of the clinical application of CGF.

Regulation of osteoblast behaviors via cross-talk between Hippo/YAP and MAPK signaling pathway under fluoride exposure.

Titanium is widely used in implant materials, while excessive fluoride may have negative effects on the osseointegration between the titanium and osteoblasts. Although the underlying mechanisms are still not clear, the mitogen-activated protein kinase (MAPK) or Yes-associated protein (YAP) signaling pathways are thought to be involved. This study evaluated the role of Hippo/YAP and MAPK signaling pathway in osteoblast behaviors under excessive fluoride exposure in vitro and in vivo. Commercially pure Ti (cp-Ti) samples were exposed to fluoride (0, 0.1, and 1.0mM NaF) for 7days. Cell adhesion was observed using a laser scanning confocal microscope. Cell viability and apoptosis were evaluated by CCK-8 assay and flow cytometry, respectively. The expressions of osteoblast markers and key molecules in MAPK and YAP pathway were detected by Western blot. In vivo studies were evaluated by histology methods in C57/BL6 mice model. Our results showed that 1.0mM NaF destroyed the passivation film on cp-Ti surface, which further inhibited the osteoblast adhesion and spreading. Meanwhile, compared to other groups, 1.0mM NaF led to a remarkable reduction in cell viability (P < 0.05), as well as increased apoptosis (P < 0.05) and downregulation of osteogenesis protein expression (P < 0.05). MAPK and YAP signaling pathways were also activated under 1.0mM NaF exposure, and JNK seemed to regulate YAP phosphorylation in response to NaF impacts on osteoblasts. In vivo fluorosis mouse model further indicated that 100ppm NaF group (high fluoride group) increased bone resorption and inhibited the nuclear translocation of YAP. The osteoblast behaviors were negatively altered under excessive fluoride, and MAPK/JNK axis contributed to YAP signaling activation in regulating NaF-induced osteoblast behaviors. KEY MESSAGES: • Excessive fluoride inhibited osteoblast behaviors and bone formation. • YAP and MAPK signaling pathways were activated in osteoblasts under fluoride exposure. • Fluoride regulated osteoblast behaviors via the cross-talk between YAP and MAPK.

UBTD1 is a mechano-regulator controlling cancer aggressiveness.

Ubiquitin domain-containing protein 1 (UBTD1) is highly evolutionary conserved and has been described to interact with E2 enzymes of the ubiquitin-proteasome system. However, its biological role and the functional significance of this interaction remain largely unknown. Here, we demonstrate that depletion of UBTD1 drastically affects the mechanical properties of epithelial cancer cells via RhoA activation and strongly promotes their aggressiveness. On a stiff matrix, UBTD1 expression is regulated by cell-cell contacts, and the protein is associated with β-catenin at cell junctions. Yes-associated protein (YAP) is a major cell mechano-transducer, and we show that UBTD1 is associated with components of the YAP degradation complex. Interestingly, UBTD1 promotes the interaction of YAP with its E3 ubiquitin ligase β-TrCP Consequently, in cancer cells, UBTD1 depletion decreases YAP ubiquitylation and triggers robust ROCK2-dependent YAP activation and downstream signaling. Data from lung and prostate cancer patients further corroborate the in cellulo results, confirming that low levels of UBTD1 are associated with poor patient survival, suggesting that biological functions of UBTD1 could be beneficial in limiting cancer progression.

Carvacrol ameliorates the progression of liver fibrosis through targeting of Hippo and TGF-β signaling pathways in carbon tetrachloride (CCl4)-induced liver fibrosis in rats

Objective: Little is known about the exact underlying molecular mechanisms of the hepatoprotective effect of carvacrol against liver fibrosis. In the current study, we aimed to investigate the effect of carvacrol on the suppression of liver fibrosis progression via regulation of yes-associated protein (YAP) and transcriptional coactivators with a PDZ-binding motif (TAZ) and transforming growth factor beta (TGF-β) pathway.Materials and methods: To fulfill our target, rats received carbon tetrachloride (CCl4) and carvacrol intraperitoneally, and orally, respectively for 10 weeks. Body weight, liver weight, serum biochemical parameters, hepatic hydroxyproline content, and histological changes were determined. Furthermore, gene expression of collagen and key elements of Hippo and TGF-β pathways were analyzed and then the protein levels of YAP, TAZ, and TGF-β were detected in liver tissue.Results: Carvacrol administration normalized liver and body weight, serum biochemical parameters and hepatic hydroxyproline in CCl4 treated rats. Also, carvacrol downregulated TAZ and TGF-β signaling pathway at transcriptional levels. Furthermore, carvacrol decreased hepatic protein levels of TGF-β, TAZ, and YAP. Low expression of TAZ and YAP were accompanied with inhibition of TGF-β signaling pathway.Conclusion: Our data clearly revealed that carvacrol suppresses the progression of liver fibrosis via targeting of TAZ, YAP, and TGF-β signaling pathway.

YAP activation promotes the transdifferentiation of cardiac fibroblasts to myofibroblasts in matrix remodeling of dilated cardiomyopathy

Yes-associated protein (YAP) is an important regulator of cellular proliferation and transdifferentiation. However, little is known about the mechanisms underlying myofibroblast transdifferentiation in dilated cardiomyopathy (DCM). We investigated the role of YAP in the pathological process of cardiac matrix remodeling. A classic model of DCM was established in BALB/c mice by immunization with porcine cardiac myosin. Cardiac fibroblasts were isolated from neonatal Sprague-Dawley rats by density gradient centrifugation. The expression levels of α-smooth muscle actin (α-SMA) and collagen volume fraction (CVF) were significantly increased in DCM mice. Angiotensin II (Ang II)-mediated YAP activation promoted the proliferation and transdifferentiation of neonatal rat cardiac fibroblasts, and this effect was significantly suppressed in the shRNA YAP + Ang II group compared with the shRNA Control + Ang II group in vitro (2.98±0.34 ×105 vs 5.52±0.82 ×105, P<0.01). Inhibition of endogenous Ang II-stimulated YAP improved the cardiac function by targeting myofibroblast transdifferentiation to attenuate matrix remodeling in vivo. In the valsartan group, left ventricular ejection fraction and fractional shortening were significantly increased compared with the DCM group (52.72±5.51% vs 44.46±3.01%, P<0.05; 34.84±3.85% vs 26.65±3.12%, P<0.01). Our study demonstrated that YAP was a regulator of cardiac myofibroblast differentiation, and regulation of YAP signaling pathway contributed to improve cardiac function of DCM mice, possibly in part by decreasing myofibroblast transdifferentiation to inhibit matrix remodeling.

Pregnane X Receptor Regulates Liver Size and Liver Cell Fate by Yes-Associated Protein Activation in Mice.

Activation of pregnane X receptor (PXR), a nuclear receptor that controls xenobiotic and endobiotic metabolism, is known to induce liver enlargement, but the molecular signals and cell types responding to PXR-induced hepatomegaly remain unknown. In this study, the effect of PXR activation on liver enlargement and cell change was evaluated in several strains of genetically modified mice and animal models. Lineage labeling using AAV-Tbg-Cre-treated Rosa26EYFP mice or Sox9-CreERT , Rosa26EYFP mice was performed and Pxr-null mice or AAV Yap short hairpin RNA (shRNA)-treated mice were used to confirm the role of PXR or yes-associated protein (YAP). Treatment with selective PXR activators induced liver enlargement and accelerated regeneration in wild-type (WT) and PXR-humanized mice, but not in Pxr-null mice, by increase of cell size, induction of a regenerative hybrid hepatocyte (HybHP) reprogramming, and promotion of hepatocyte and HybHP proliferation. Mechanistically, PXR interacted with YAP and PXR activation induced nuclear translocation of YAP. Blockade of YAP abolished PXR-induced liver enlargement in mice. Conclusion: These findings revealed a function of PXR in enlarging liver size and changing liver cell fate by activation of the YAP signaling pathway. These results have implications for understanding the physiological functions of PXR and suggest the potential for manipulation of liver size and liver cell fate.

Hypermethylated in cancer 1 (HIC1) suppresses bladder cancer progression by targeting yes-associated protein (YAP) pathway.

Bladder cancer (BCa) is the most common malignant tumor in the urinary system. Growing evidence suggests that as a tumor suppressor gene, hypermethylated in cancer 1 (HIC1) is correlated with various malignancies in the modulation of tumor progression. This study aims to investigate the effect of HIC1 on regulating the proliferation, migration, and invasion of BCa. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot (WB) were used to evaluate the expression of HIC1 messenger RNA and protein in human BCa tissues and cells. Proliferation, migration and invasion assays, and flow cytometry assay were performed to assess the biological functional role of HIC1 in BCa. Co-immunoprecipitation (Co-IP) examined the protein-protein interaction. The signaling pathways involved in the mode of action of HIC1 in BCa were also investigated. HIC1 was found downregulated in tested samples. Cloning formation assay and cell-proliferation activity analysis showed that overexpression of HIC1 significantly inhibited the proliferation of BCa cells, while knockdown led to the opposite, namely the promotion of the proliferation. Flow cytometry assay confirmed the arrest of the cell cycle at the G1 phase with overexpression of HIC1 observed. Moreover, HIC1 inhibited migration and invasion of BCa. Co-IP showed the binding between YAP (yes-associated protein) and TEAD (TEA domain/transcription enhancer factor family members) as well as the cancerostatic activity of HIC1, partially manifested via its negative regulation of YAP signaling pathway. Our data unprecedently showed that HIC1 was responsible for the inhibition of proliferation, migration, and invasion of BCa via the YAP signaling pathway. These findings suggested that therapeutic strategies regulating HIC1 expression might provide effective treatments for BCa.

Cyclic Stretch Enhances Osteogenic Differentiation of Human Periodontal Ligament Cells via YAP Activation.

Periodontal remodeling and alveolar bone resorption and formation play essential roles during orthodontic tooth movement (OTM). In the process, human periodontal ligament cells (HPDLCs) sense and respond to orthodontic forces, contributing to the alveolar bone formation. However, the underlying mechanism in this process is not fully elucidated. In the present study, cyclic stress stimulus was applied on HPDLCs to mimic the orthodontic forces during OTM. Our results demonstrated that cyclic stretch promoted the osteogenic differentiation of HPDLCs. Moreover, our data suggested that yes-associated protein (YAP), the Hippo pathway effector, which also involved in mechanical signaling transduction, was activated as we found that the nuclear translocation of YAP was significantly increased in the cyclic stress treated HPDLCs. The mRNA expression of CTGF and CYR61, the target genes of YAP, was also remarkably increased. Furthermore, knockdown of YAP suppressed the cyclic stretch induced osteogenesis in HPDLCs, while overexpression of YAP in HPDLCs enhanced osteogenesis. We also noticed that YAP activities could be suppressed by the ROCK and nonmuscle myosin II inhibitors, Y-27632 and Blebbistatin. The inhibitors also significantly inhibited the cyclic stretch induced osteogenesis in HPDLCs. Finally, in the murine OTM model, our results revealed that YAP was upregulated and nuclearly translocated in the PDLCs at the tension side. In summary, our present study demonstrated that cytoskeleton remodeling induced activation of YAP signaling pathway was crucial for the cyclic stretch-induced osteogenesis of HPDLCs, which might play important roles during OTM.

Invited commentary

Neointimal hyperplasia (NIH) is the proliferation and migration of vascular smooth muscle cells primarily in the intima, resulting in the thickening of the arterial wall and decreased arterial lumen. NIH is a significant problem after revascularization that can lead to significant graft and stent failures. Novel research investigating pathways that are responsible for NIH may provide insight into the pathophysiologic process and effective treatment options. There are currently drug-eluting stents based on paclitaxel and sirolimus, which are designed to inhibit smooth muscle cell proliferation. Although they are effective at reducing NIH, in-stent restenosis and thrombosis continue to occur. This may be due to the nonspecific effects of the drug to the target pathways/cells or incomplete inhibition of the pathways responsible for NIH. In this very important study, the authors investigate the inhibition of Rho GTPase, specifically RhoA and its effect on Hippo pathway-related genes and YAP transcription coactivator. YAP (Yes-associated protein) is a protein that acts as a transcriptional regulator by activating the transcription of genes involved in cell proliferation and suppressing apoptotic genes. Initially, the study demonstrated that active RhoA expression affects the smooth muscle cell synthetic phenotype and decreases the contractile phenotype. Inhibition of RhoA by rhosin decreased cell proliferation but had no effect on apoptosis. The inhibition of RhoA-guanosine triphosphate involved the knockdown of cyclin D and affected the majority of cells in the S phase of the cell cycle. Next, the authors demonstrated that YAP plays an important role in the regulation of smooth muscle cell phenotypic modulation and is affected by RhoA, whereby RhoA inhibition reduces the expression of both cytoplasmic and nuclear YAP. Finally, the authors tested whether inhibition of RhoA in a carotid rabbit model would decrease NIH, using rhosin jelly-coated stents to inhibit RhoA. Compared with bare-metal stents, the rhosin-coated stents had less NIH, and cellular analysis demonstrated that the smooth muscle cell contractile phenotype was induced and the synthetic phenotype was suppressed. These effects were mitigated when active YAP lentivirus was instilled into the RhoA-inhibited stent carotid section for 30 minutes, indicating the involvement of YAP in switching the smooth muscle cell phenotype from contractile to synthetic, with increased NIH. In summary, the data demonstrated that the RhoA inhibitor-eluting stent attenuated in-stent restenosis through the YAP signaling pathway evaluated at 6 months. These novel mechanistic discoveries of RhoA and YAP involved in NIH in the context of arterial stents offer an exciting and promising area for clinical trials using RhoA inhibitor drug-eluting stents. Further work is necessary to validate the in vitro and in vivo animal studies from this study, to translate the basic scientific research of RhoA inhibition and decreased NIH, and to determine the effectiveness and durability in human trials. The opinions or views expressed in this commentary are those of the author and do not necessarily reflect the opinions or recommendations of the Journal of Vascular Surgery or the Society for Vascular Surgery. RhoA inhibitor-eluting stent attenuates restenosis by inhibiting YAP signalingJournal of Vascular SurgeryVol. 69Issue 5PreviewCurrent drug-eluting stent (DES) treatment is promising, but it still has the drawback of in-stent restenosis, which remains a clinically relevant problem. Efforts should be made to discover new signaling molecules and novel potential targets for the prevention of arterial restenosis. In this study, we fabricated a novel DES targeting the RhoA pathway and further examined this promising strategy in vitro and in a rabbit carotid model. Full-Text PDF Open Archive

Pathogenesis of non-alcoholic fatty liver disease mediated by YAP.

This study aimed to investigate the mechanism of the interaction between Yes-associated protein (YAP) and transforming growth factor-β (TGF-β)/Smad signaling pathways in the development of non-alcoholic fatty liver disease (NAFLD). Serum samples of monkeys with biopsy-proven NAFLD and healthy normal monkeys were used to measure fasting plasma glucose (FPG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG) and albumin (ALB) with the BECKMAN CX5 PRO. Hematoxylin-eosin staining (H&E) was used for pathologic analysis, Masson trichrome staining was used to assess for fibrosis staging, and Oil Red O staining was used to detect lipid droplet deposition. According to an NAFLD activity score of <4 points and >4 points, the samples were divided into groups: the steatosis group and fibrosing NASH group. Furthermore, monkeys with a fibrosis stage <2 were assigned to the mild fibrosis group, while monkeys with fibrosis stage ≥2 were assigned to the significant fibrosis group. Moreover, the fibrosis stage was subdivided as follows: stages 1a, 1c and 2-3. Immunohistochemistry and real-time quantitative PCR were used to quantify protein and gene expression, respectively. In the present study, 54 monkeys with NAFLD and 23 normal monkeys were recruited. Serum FPG and TG levels were higher in fibrosing NASH monkeys compared with simple steatosis and normal monkeys, and differences between simple steatosis and normal monkeys were not statistically significant (p>0.05). YAP increased in NAFLD, which mainly localized in the nuclei of hepatocytes, perivascular cells and bile duct cells; the accumulation of YAP correlated with the severity of hepatocyte injury. Compared with normal monkeys, the expression of TGF-β, α-smooth muscle actin (α-SMA), Drosophila mothers against decapentaplegic protein 3 (Smad3) and connective tissue growth factor (CTGF) in the liver of simple steatosis monkeys significantly increased (p<0.01). Compared with simple steatosis monkeys, the expression of TGF-β, α-SMA, Smad3 and CTGF in fibrosing NASH significantly increased (p<0.01). However, the expression of Drosophila mothers against decapentaplegic protein 7 (Smad7) in the liver of fibrosing NASH monkeys significantly decreased (p<0.01). With the severity of liver fibrosis, the expression of TGF-β, α-SMA, Smad3 and CTGF gradually increased, and the difference was statistically significant (p<0.01). However, there was no significant difference in the expression of Smad3 between fibrosis stage 1a and 1c. Compared with normal monkeys, the expression of Smad7 in the liver of monkeys with fibrosis significantly decreased (p<0.01), but was significantly higher at fibrosis stage 1c than at fibrosis stage 1a and 2. The YAP and TGF-β signaling pathways and the interaction between them promote the development and progression of NAFLD.

A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

Herein, we have identified cross-talk between the Hippo and fibroblast growth factor receptor (FGFR) oncogenic signaling pathways in cholangiocarcinoma (CCA). Yes-associated protein (YAP) nuclear localization and up-regulation of canonical target genes was observed in CCA cell lines and a patient-derived xenograft (PDX). Expression of FGFR1, -2, and -4 was identified in human CCA cell lines, driven, in part, by YAP coactivation of TBX5. In turn, FGFR signaling in a cell line with minimal basal YAP expression induced its cellular protein expression and nuclear localization. Treatment of YAP-positive CCA cell lines with BGJ398, a pan-FGFR inhibitor, resulted in a decrease in YAP activation. FGFR activation of YAP appears to be driven largely by FGF5 activation of FGFR2, as siRNA silencing of this ligand or receptor, respectively, inhibited YAP nuclear localization. BGJ398 treatment of YAP-expressing cells induced cell death due to Mcl-1 depletion. In a YAP-associated mouse model of CCA, expression of FGFR 1, 2, and 4 was also significantly increased. Accordingly, BGJ398 treatment was tumor-suppressive in this model and in a YAP-positive PDX model. These preclinical data suggest not only that the YAP and Hippo signaling pathways culminate in an Mcl-1-regulated tumor survival pathway but also that nuclear YAP expression may be a biomarker to employ in FGFR-directed therapy.

Targeting YAP and Hippo signaling pathway in liver cancer

Importance of the field: The Hippo signaling pathway plays pivotal roles in controlling both cell growth and organ size, emerging as a new paradigm in tumor suppression. Yes-associated protein (YAP) functions as a potent transcription co-activator and is a major downstream target tightly regulated by the Hippo pathway. Inactivation of the Hippo signaling induces YAP-mediated activation of various target genes that functionally causes cellular proliferation and outgrowth of organ size. Recently, YAP has been implicated as a bona fide oncogene in solid tumors, but little is known about its exact molecular mechanism in carcinogenesis.Areas covered in this review: We discuss the latest important findings in the Hippo signaling pathway and the possible means of developing potential cancer therapeutics by targeting multiple sites along the Hippo pathway.What the reader will gain: An overview of the emerging roles of YAP and Hippo signaling in oncogenesis and the possible ways of developing cancer therapies against the pathway components, downstream targets or interconnected pathways.Take home message: YAP is a key oncogenic driver in liver carcinogenesis and deregulation of the Hippo pathway causes tumor formation and malignancy. Targeting YAP and cognate downstream signaling targets may have clinical utility in cancer therapies.