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Abstract Colorectal cancer (CRC) is the third most common cancer type and the second highest mortality rate among cancers. However, the mechanisms underlying CRC progression remain to be fully understood. In this work, a recently identified m6A‐modified RNA reader protein Proline‐rich Coiled‐coil 2a (PRRC2A) is markedly upregulated in CRC, and intestinal epithelium‐specific deletion of Prrc2a significantly suppressed tumor cell growth, stemness, and migratory capacity, while its overexpression promoted these behaviors. Through multiomics analysis, PRRC2A directly targeted CSNK1E (encoding CK1ε), maintaining its RNA stability in an m6A‐dependent manner, and that elevated CK1ε can concomitantly result in activation of the WNT and YAP signaling pathways. Interestingly, PRRC2A is directly regulated by the transcription factor ATF1 in its promoter. In summary, the work reveals a novel mechanism by which m6A reader PRRC2A promotes colorectal cancer progression via CK1ε and aberrant upregulation of WNT and YAP signaling. Therefore, PRRC2A and CK1ε can be potential therapeutic targets for treating CRC.

Copyright of Chinese Journal of Cancer Biotherapy is the property of Editorial Office of Chinese Journal of Cancer Biotherapy and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Disruption of iron homeostasis plays a negative role in follicle development. The dynamic changes in follicle growth are dependent on Hippo/YAP signaling and mechanical forces. However, little is known about the liaison between iron overload and the Hippo/YAP signalling pathway in term of folliculogenesis. Here, based on the available evidence, we established a hypothesized model linking excessive iron, extracellular matrix (ECM), transforming growth factor-b (TGF-β) and Hippo/Yes-associated protein (YAP) signal regarding follicle development. Hypothetically, the TGF-b signal and iron overload may play a synergistic role in ECM production via YAP. We speculate that the dynamic homeostasis of follicular iron interacts with YAP, increasing the risk of ovarian reserve loss and may enhance the sensitivity of follicles to accumulated iron. Hence, therapeutic interventions targeting iron metabolism disorders, and Hippo/YAP signal may alter the consequences of the impaired developmental process based on our hypothesis, which provides potential targets and inspiration for further drug discovery and development applied to clinical treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] • Sorafenib reduces liver fibrosis and HSCs activation by triggering ferroptosis. • The ferroptosis of HSCs is related to the regulation of ASIC1a. • ASIC1a regulates HSCs ferroptosis by regulating the calcium ion-dependent Hippo/YAP pathway. Liver fibrosis is a sustained process of liver tissue damage and repair caused by various physiological and pathological factors, with the activation and proliferation of hepatic stellate cells being central. Therefore, understanding and clarifying the relevant mechanisms of hepatic stellate cell activation and death is of great clinical significance for the treatment of liver fibrosis diseases. In vivo, recombinant adeno-associated virus was used to infect the liver of experimental mice, overexpressing ASIC1a, and based on this, a liver fibrosis model treated with sorafenib was constructed. In vitro, using RNA plasmid technology to transfect HSC-T6 cells, ASIC1a was overexpressed or silenced in the cells, and on this basis, PDGF-BB and Sorafenib were used to stimulate HSC-T6 cells, causing activated HSC-T6 to undergo ferroptosis. The ferroptosis inducers Sorafenib and erastin can induce ferroptosis in HSCs, effectively inhibiting or reversing the progression of liver fibrosis. We found that the expression level of ASIC1a was significantly reduced in the livers of mice with liver fibrosis treated with Sorafenib. After treatment with an adeno-associated virus overexpressing ASIC1a, the therapeutic effect of Sorafenib was inhibited, and the level of ferroptosis induced by Sorafenib was also inhibited. The induction of ferroptosis in hepatic stellate cells in vitro depends on the presence of ASIC1a. By further exploring the potential mechanism, we observed that the overexpression of ASIC1a can promote an increase in YAP nuclear translocation, thereby regulating the activity of Hippo/YAP pathway signaling. After treatment with Sorafenib, the influx of Ca2+ significantly increased when ASIC1a was overexpressed, and BAPTA-AM intervention eliminated the intracellular Ca2+ accumulation induced by ASIC1a overexpression. This indicated that the activation of YAP depends on the calcium ion influx induced by ASIC1a, which regulates ferroptosis in hepatic stellate cells by regulating the calcium ion-dependent Hippo/YAP pathway. [ABSTRACT FROM AUTHOR]

Copyright of Journal of China Medical University is the property of Journal of China Medical University Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aim: Hypertensive nephropathy is embodied by kidney tissue fibrosis and glomerular sclerosis, as well as renal inflammation. The Hippo/YAP (yes‐associated protein, YAP) axis has been reported to promote inflammation and fibrosis and may participate in the pathogenesis of heart, vascular and renal injuries. However, the role of the Hippo/YAP pathway in hypertensive renal injury has not been reported so far. We explored the role of the Hippo/YAP signalling pathway in hypertensive renal injury and the effect of peptide 17 on its effects. Methods: Histopathological analyses were performed based on the Masson and Haematoxylin/eosin (HE) staining approaches. Biochemical indexes were determined and immunofluorescence and western blotting were used to detect protein expression levels. The mRNA expression levels were determined by qRT‐PCR. Results: Our results showed that peptide 17 reduced the systolic blood pressure (SBP) and urine protein/creatinine ratio in hypertensive rats. In addition, peptide 17 reduced the histopathological damage of kidneys in spontaneously hypertensive rats (SHRs). Moreover, peptide 17 downregulated genes in the Hippo/Yap pathway in kidney tissue of SHRs and Ang II‐treated kidney cells. The expression levels of inflammatory factors TNF‐α, IL‐1β and MCP‐1 and the pro‐fibrotic factors TGF‐β1, fibronectin, and CTGF were increased in the kidney of hypertensive rats, but reversed by peptide 17 treatment. Silencing of YAP had effect similar to that of peptide 17 in vivo and in vitro. Conclusion: Peptide 17 alleviates early renal injury in hypertension by regulating the Hippo/YAP signalling pathway. These findings may be useful in the treatment of hypertensive renal injury. Summary at a Glance: Herein, we explored the effect of peptide 17 on hypertensive renal injury and its mechanism of action. The results hinted that peptide 17 attenuated the deleterious inflammatory and fibrotic effects of hypertensive renal injury via downregulating the Hippo/YAP axis. These findings may be relevant for treating hypertensive nephropathy. [ABSTRACT FROM AUTHOR]

In multicellular eukaryotic organisms, the initiation of DNA replication occurs asynchronously throughout S-phase according to a regulated replication timing program. Here, using Xenopus egg extracts, we showed that Yap (Yes-associated protein 1), a downstream effector of the Hippo signalling pathway, is required for the control of DNA replication dynamics. We found that Yap is recruited to chromatin at the start of DNA replication and identified Rif1, a major regulator of the DNA replication timing program, as a novel Yap binding protein. Furthermore, we show that either Yap or Rif1 depletion accelerates DNA replication dynamics by increasing the number of activated replication origins. In Xenopus embryos, using a Trim-Away approach during cleavage stages devoid of transcription, we found that either Yap or Rif1 depletion triggers an acceleration of cell divisions, suggesting a shorter S-phase by alterations of the replication program. Finally, our data show that Rif1 knockdown leads to defects in the partitioning of early versus late replication foci in retinal stem cells, as we previously showed for Yap. Altogether, our findings unveil a non-transcriptional role for Yap in regulating replication dynamics. We propose that Yap and Rif1 function as brakes to control the DNA replication program in early embryos and post-embryonic stem cells.

IL-6 family cytokine leukaemia inhibitory factor (LIF) study has deciphered a variety of effects, in physiology as well as pathology. Despite the sudden arousal in LIF interest in cancers, its study in the gastric cancer (GC) context has been put aside. Only few related studies can be found in literature, most of them investigating IL-6/STAT3 signalling in GC, and not the particular LIF/LIFRβ signalisation. LIF/LIFR has opposing effects depending on the signalling pathways involved. This review relates the pro- and anti-tumorigenic aspects of LIF/LIFR in GC, taking also into account facts from other types of cancer. A better understanding of these issues would undoubtedly help postulate interesting hypotheses and perspectives for future LIF/LIFR study and its use in GC therapies, where options tend to be limited in number and efficiency. [ABSTRACT FROM AUTHOR]

Cells are constantly exposed to various mechanical forces, including hydrostatic pressure, cyclic stretch, fluid shear stress, and extracellular matrix stiffness. Mechanical cues can be translated into the cell-specific transcriptional process by a cellular mechanic-transducer. Evidence suggests that mechanical signals assist activated intracellular signal transduction pathways and the relative phenotypic adaptation to coordinate cell behavior and disease appropriately. The Hippo/yes-associated protein (YAP) signaling pathway is regulated in response to numerous mechanical stimuli. It plays an important role in the mechanotransduction mechanism, which converts mechanical forces to cascades of molecular signaling to modulate gene expression. This review summarizes the recent findings relevant to the Hippo/YAP pathway-based mechanotransduction in cell behavior and maintaining blood vessels, as well as cardiovascular disease. • How the mechanical cues are sensed and transduced at the molecular level to regulate gene expression remained elusive. • Hippo/YAP functioned as a mechanotransduction switch of mechanical forces, and translated them into transcriptional process. • Hippo/YAP function as a mechanotransducer in cell behavior, blood vessels maintenance, and cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Yes-associated protein (YAP) and its associated coactivator of PDZ-binding motif (TAZ) are co-transcriptional regulators and down effectors of the Hippo signaling pathway. Recent studies have shown that the Hippo/YAP signaling pathway may play a role in mediating vascular homeostasis. This study investigated the role of YAP/TAZ in endothelial dysfunction and vascular inflammation in angiotensin (Ang)II hypertensive mice. The infusion of AngII (1.1 mg/kg/day by mini-pump) for 3 weeks induced the activation of YAP/TAZ, manifested by decreased cytosolic phosphor-YAP and phosphor-TAZ, and increased YAP/TAZ nuclear translocation, which were prevented by YAP/TAZ inhibitor verteporfin. AngII significantly increased systolic blood pressure (SBP), macrophage infiltration, and expressions of proinflammatory cytokines, and impaired endothelial function in the aorta of the mice. Treatment with verteporfin improved endothelial function and reduced vascular inflammation with a mild reduction in SBP. AngII also induced YAP/TAZ activation in human umbilical vein endothelial cells in vitro, which were prevented by LB-100, an inhibitor of protein phosphatase 2A (PP2A, a major dephosphorylase). Treatment with LB-100 reversed AngII-induced proinflammatory cytokine expression and impairment of phosphor-eNOS expression in vitro. Our results suggest that AngII induces YAP/TAZ activation via PP2A-dependent dephosphorylation, which may contribute to the impairment of endothelial function and the induction of vascular inflammation in hypertension. YAP/TAZ may be a new target for hypertensive vascular injury.

Acute myocardial infarction (AMI) is the main cause of death in the whole world. This study aimed to investigate whether forkhead box O4 (FoxO4) could negatively modulate ubiquitin specific peptidase 10 (USP10) transcription to aggravate the apoptosis and oxidative stress of hypoxia/reoxygenation (H/R)-induced cardiomyocytes through Hippo/YAP pathway. mRNA expression as well as protein expressions of USP10 and FoxO4 in H9C2 cells after H/R induction or transfection were respectively detected by Reverse transcription-quantitative (RT-q) PCR analysis and Western blot. The viability and apoptosis of H9C2 cells after H/R induction or transfection were respectively detected by CCK-8 and TUNEL assays. The expressions of lactate dehydrogenase (LDH), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in H9C2 cells after H/R induction or transfection were analyzed using appropriate kits and intracellular reactive oxygen species (ROS) levels were detected using a ROS Assay Kit. Dual luciferase reporter assay and Chromatin Immunoprecipitation (ChIP) have adopted to confirm the combination of USP10 and FoxO4. Western blot was also used to analyze the expression of apoptosis-related proteins and Hippo/YAP pathway-related proteins. As a result, USP10 expression was decreased in H/R-induced H9C2 cells in a time-dependent manner. USP10 overexpression increased the viability and suppressed the apoptosis and oxidative stress of H/R-induced H9C2 cells. In addition, FoxO4 modulated USP10 transcription. FoxO4 expression was increased in H9C2 cells induced by H/R. FoxO4 overexpression could reverse the protective effects of USP10 overexpression on H/R-induced H9C2 cells by regulating the Hippo/YAP signaling pathway. In conclusion, FoxO4 negatively modulated USP10 transcription to aggravate the apoptosis and oxidative stress of H/R-induced H9C2 cells via blocking Hippo/YAP pathway. [ABSTRACT FROM AUTHOR]

Yes-associated protein (YAP) and its associated coactivator of PDZ-binding motif (TAZ) are co-transcriptional regulators and down effectors of the Hippo signaling pathway. Recent studies have shown that the Hippo/YAP signaling pathway may play a role in mediating vascular homeostasis. This study investigated the role of YAP/TAZ in endothelial dysfunction and vascular inflammation in angiotensin (Ang)II hypertensive mice. The infusion of AngII (1.1 mg/kg/day by mini-pump) for 3 weeks induced the activation of YAP/TAZ, manifested by decreased cytosolic phosphor-YAP and phosphor-TAZ, and increased YAP/TAZ nuclear translocation, which were prevented by YAP/TAZ inhibitor verteporfin. AngII significantly increased systolic blood pressure (SBP), macrophage infiltration, and expressions of proinflammatory cytokines, and impaired endothelial function in the aorta of the mice. Treatment with verteporfin improved endothelial function and reduced vascular inflammation with a mild reduction in SBP. AngII also induced YAP/TAZ activation in human umbilical vein endothelial cells in vitro , which were prevented by LB-100, an inhibitor of protein phosphatase 2A (PP2A, a major dephosphorylase). Treatment with LB-100 reversed AngII-induced proinflammatory cytokine expression and impairment of phosphor-eNOS expression in vitro. Our results suggest that AngII induces YAP/TAZ activation via PP2A-dependent dephosphorylation, which may contribute to the impairment of endothelial function and the induction of vascular inflammation in hypertension. YAP/TAZ may be a new target for hypertensive vascular injury. [ABSTRACT FROM AUTHOR]

The Hippo/Yap pathway is a well-conserved signaling cascade that regulates cell proliferation and differentiation to control organ size and stem/progenitor cell behavior. Following airway injury, Yap was dynamically regulated in regenerating airway epithelial cells. To determine the role of Hippo signaling in the lung, the mammalian Hippo kinases, Mst1 and Mst2, were deleted in epithelial cells of the embryonic and mature mouse lung. Mst1/2 deletion in the fetal lung enhanced proliferation and inhibited sacculation and epithelial cell differentiation. The transcriptional inhibition of cell proliferation and activation of differentiation during normal perinatal lung maturation were inversely regulated following embryonic Mst1/2 deletion. Ablation of Mst1/2 from bronchiolar epithelial cells in the adult lung caused airway hyperplasia and altered differentiation. Inhibitory Yap phosphorylation was decreased and Yap nuclear localization and transcriptional targets were increased after Mst1/2 deletion, consistent with canonical Hippo/Yap signaling. YAP potentiated cell proliferation and inhibited differentiation of human bronchial epithelial cells in vitro. Loss of Mst1/2 and expression of YAP regulated transcriptional targets controlling cell proliferation and differentiation, including Ajuba LIM protein. Ajuba was required for the effects of YAP on cell proliferation in vitro. Hippo/Yap signaling regulates Ajuba and controls proliferation and differentiation of lung epithelial progenitor cells.

The presence of metal ions, such as titanium (Ti) ions, is toxic to adjacent tissues of implants. Indeed, Ti ions may induce an inflammatory response through the NF‐κB pathway, thus causing damage to soft and hard tissues. The involvement of Yes‐associated protein (YAP), a key factor of the Hippo pathway, in an immuno‐inflammatory response has been confirmed, whereas its role in Ti ion‐mediated inflammation has not been elucidated. Therefore, this study aimed to investigate the role of signal crosstalk between the Hippo/YAP and NF‐κB signaling pathways in the pro‐inflammatory effect of Ti ions on macrophages. In our work, RAW264.7 cells were cocultured with Ti ions. The migration capacity of macrophages under Ti ion exposure was measured by transwell assay. Western blot analysis was used to detect the expressions of related proteins. Polymerase chain reaction was used to evaluate the expression of pro‐inflammatory cytokines. The nucleus translocation of YAP and P65 was visualized and analyzed via immunofluorescence staining. The results showed that the migration of macrophages was promoted under Ti ion exposure. Ten parts per million Ti ions induced nuclear expression of YAP and activated the NF‐κB pathway, which finally upregulated the expression of pro‐inflammatory cytokines in macrophages. Moreover, the inhibition of the NF‐κB pathway rescued the reduction of YAP expression under Ti ion exposure. Most importantly, the overexpression of YAP exacerbated the inflammatory response mediated by Ti ions through the NF‐κB pathway. In summary, this study explored the mechanism of Hippo‐YAP/NF‐κB pathway crosstalk involved in the regulation of macrophage behaviors under Ti ion exposure. Titanium (Ti) ions are toxic to adjacent tissues of implants, but the underlying mechanism has not been elucidated. This study found that Ti ions promoted the migration of macrophages and activated macrophages to release pro‐inflammatory cytokines. During this process, the Hippo‐YAP and NF‐κB pathways were activated in macrophages. Further studies showed that the Hippo‐YAP and NF‐κB signaling pathways crosstalk was involved in the regulation of macrophage behavior under Ti ion exposure. The present study provided a molecular mechanism for Ti ion‐induced inflammation. [ABSTRACT FROM AUTHOR]

Diabetic angiopathy, which includes diabetic kidney disease (DKD), cardio-cerebrovascular disease, and diabetic retinopathy (DR) among other diseases, is one of the most common complications affecting diabetic patients. Among these, DKD, which is a major cause of morbidity and mortality, affects about 40% of diabetic patients. Similarly, DR involves retinal neovascularization and neurodegeneration as a result of chronic hyperglycemia and is the main cause of visual impairment and blindness. In addition, inflammation also promotes atherosclerosis and diabetes, with atherosclerosis-related cardiovascular diseases being often a main cause of disability or death in diabetic patients. Given that vascular diseases caused by diabetes negatively impact human health, it is therefore important to identify appropriate treatments. In this context, some studies have found that the Hippo/Yes-associated protein (YAP) pathway is a highly evolutionarily conserved protein kinase signal pathway that regulates organ growth and size through its effector signaling pathway Transcriptional co-Activator with PDZ-binding motif (TAZ) and its YAP. YAP is a key factor in the Hippo pathway. The activation of YAP regulates gluconeogenesis, thereby regulating glucose tolerance levels; silencing the YAP gene thereby prevents the formation of glomerular fibrosis. YAP can combine with TEA domain family members to regulate the proliferation and migration of retinal vascular endothelial cells (ECs), so YAP plays a prominent role in the formation and pathology of retinal vessels. In addition, YAP/TAZ activation and translocation to the nucleus promote endothelial inflammation and monocyte-EC attachment, which can increase diabetes-induced cardiovascular atherosclerosis. Hippo/YAP signaling pathway provides a potential therapeutic target for diabetic angiopathy, which can prevent the progression of diabetes to DR and improve renal fibrosis and cardio-vascular atherosclerosis., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Liver fibrosis is a reversible pathological process accompanied by abnormal inflammation, and its end-stage cirrhosis is responsible for high morbidity and mortality worldwide. This study was to investigate the effect of Magnesium isoglycyrrhizinate (MgIG) on liver fibrosis and inflammation, and to further clarify molecular mechanism. We found that MgIG treatment significantly alleviated carbon tetrachloride (CCl 4 )-induced liver fibrosis and HSC activation by regulating TGF-β signaling and MMP/TIMP systems. In addition, MgIG treatment significantly inhibited the inflammatory response of liver fibrosis in mice characterized by reduced pro-inflammatory factors expression and increased anti-inflammatory factors expression. Interestingly, experiments in vitro also showed that MgIG treatment significantly reduced the expression of hepatic stellate cell (HSC) activation markers. Besides, MgIG treatment not only inhibited the expression of pro-inflammatory factors, but also promoted the production of anti-inflammatory factors in activated HSCs. Importantly, treatment with MgIG inhibited Hippo/Yap signaling pathway, which was a potential mechanism for MgIG-induced anti-inflammatory effects. The overexpression of Hippo/Yap signaling effector YAP completely impaired MgIG-induced anti-inflammatory and anti-fibrotic effects. Taken together, these results provide novel implications to reveal the molecular mechanism of the anti-inflammatory properties induced by MgIG, by which points to the possibility of using MgIG to treat liver fibrosis. [ABSTRACT FROM AUTHOR]

The adult frog retina retains a reservoir of active neural stem cells that contribute to continuous eye growth throughout life. We found that Yap, a downstream effector of the Hippo pathway, is specifically expressed in these stem cells. Yap knock-down leads to an accelerated S-phase and an abnormal progression of DNA replication, a phenotype likely mediated by upregulation of c-Myc. This is associated with an increased occurrence of DNA damage and eventually p53-p21 pathway-mediated cell death. Finally, we identified PKNOX1, a transcription factor involved in the maintenance of genomic stability, as a functional and physical interactant of YAP. Altogether, we propose that YAP is required in adult retinal stem cells to regulate the temporal firing of replication origins and quality control of replicated DNA. Our data reinforce the view that specific mechanisms dedicated to S-phase control are at work in stem cells to protect them from genomic instability.

Radiotherapy is an indispensable modality in comprehensive treatment of breast cancer. However, inherent or acquired radiation resistance of tumors compromises the efficacy of radiotherapy. Herein, we found that CD146, a unique epithelial-to-mesenchymal transition (EMT) inducer particularly highly expressed in triple-negative breast cancer (TNBC), is dramatically induced by ionizing irradiation. Further study demonstrates that CD146 promotes tumor cell radioresistance in vitro and in vivo. Specifically, we report the underlying mechanism that CD146 activates YAP protein, and drives its relocation from plasma to nucleus by regulating LATS1, and promoting abnormal DNA damage repair, as well as inducing EMT and stemness. Moreover, CD146 can form a novel co-receptor complex with integrin β1 and induces radiation-resistance in breast cancer. Dual inhibition of CD146 and integrin β1 activity had a stronger inhibitory effect on breast cancer tumor growth and synergistically increased their sensitivity to radiotherapy. This study identifies a unique function of CD146 implicates with integrin β1 and YAP signaling, contributing to radiation resistance. Targeted therapy against CD146 or inhibition of integrin β1 is a potential strategy to overcome radiotherapeutic resistance of breast cancer. [ABSTRACT FROM AUTHOR]

Background: Wu-Mei-Wan (WMW), a traditional Chinese medicine, has been applied in the treatment of gastrointestinal diseases with long-term diarrhea and mucopurulent bloody stool as the main symptoms since ancient times. Studies have shown that WMW inhibits intestinal inflammation, repairs damaged intestinal mucosa, resists colon necrosis, and resists intestinal fibrosis. However, the specific mechanism of action is not yet clear.Objective: Ulcerative colitis (UC), an intestinal disease with intestinal inflammation and injury as the main pathological manifestations, is one of the high-risk factors for colon cancer. Inhibiting the inflammatory response and promoting colonic epithelial repair are critical to the treatment of UC. However, there is still a lack of remedies with satisfactory curative effects. In this study, the role of WMW in dextran sulfate sodium (DSS)-induced colitis in mice and its related mechanisms are discussed from two aspects: intestinal inflammation and tissue repair.Methods: DSS was used to induce colitis in mice and the therapeutic effect of WMW was analyzed by disease activity score, histopathological score, colon length measurement, serum cytokine detection, and flow cytometry. Macrophage activation and colonic stem cell proliferation were observed by immunohistochemistry. The expression of critical molecules in macrophage activation and colonic stem cell proliferation signaling pathways in colon tissue was detected with immunohistochemistry, immunofluorescence staining, RT-qPCR, and Western blot.Results: WMW could significantly alleviate DSS-induced colitis. We showed that WMW could reduce disease activity, reduce pathological scores, limit weight loss, inhibit colon shortening, inhibit inflammatory factor secretion, attenuate inflammatory response, and promote the repair of damaged colonic epithelium. WMW inhibited the activation of colonic macrophages, and its mechanism might be inhibiting the Notch/NF-κB/NLRP3 pathway; WMW promoted the proliferation of colonic stem cells, and its mechanism was associated with the regulation of the Hippo/YAP signaling pathway.Conclusion: The results of this study suggested that WMW could treat UC via a mechanism that inhibited the intestinal inflammatory response and repaired damaged intestinal mucosa. [ABSTRACT FROM AUTHOR]

Abstract: Emerging studies have revealed that Malat1 is overexpressed in many malignant diseases, including liver cancer, and contributes to enhancing cell migration or facilitating proliferation. However, the mechanism underlying its regulation has largely remained elusive. Here, we characterised the oncoprotein Yes-associated protein (YAP), which up-regulated metastasis-associated lung adenocarcinoma transcript 1 (Malat1) expression at both transcriptional and post-transcriptional levels, whereas serine/arginine-rich splicing factor 1 (SRSF1) played an opposing role. SRSF1 inhibited YAP activity by preventing its co-occupation with TCF/β-catenin on the Malat1 promoter. In contrast, overexpression of YAP impaired the nuclear retention of both SRSF1 and itself via an interaction with Angiomotin (AMOT). This effect removed the inhibitory role of SRSF1 on Malat1 in the nucleus. Furthermore, higher expression of YAP was consistent with a lower SRSF1 nuclear accumulation in human liver cancer tissues. We also revealed that overexpression of YAP combined with a knockdown of SRSF1 resulted in conspicuously enhanced transwell cell mobility, accelerated tumour growth rate, and loss of body weight in a tail vein-injected mouse models. Taken together, these data provided a novel mechanism underlying the balance between SRSF1, YAP and Malat1 and uncovered a new role of YAP in regulating long non-coding RNA (lncRNA). Thus, disrupting the interaction between YAP and SRSF1 may serve as a crucial therapeutic method in liver cancer. [Copyright &y& Elsevier]

The Hippo signaling pathway has been implicated as a conserved regulator of organ size in both Drosophila and mammals. Yes-associated protein (YAP), the central component of the Hippo signaling cascade, functions as an oncogene in several malignancies. Ovarian granulosa cell tumors (GCT) are characterized by enlargement of the ovary, excess production of estrogen, a high frequency of recurrence, and the potential for malignancy and metastasis. Whether the Hippo pathway plays a role in the pathogenesis of GCT is unknown. This study was conducted to examine the expression of YAP in human adult GCTs and to determine the role of YAP in the proliferation and steroidogenesis of GCT cells. Compared with age-matched normal human ovaries, GCT tissues exhibited higher levels of YAP expression. YAP protein was predominantly expressed in the nucleus of tumor cells, whereas the non-tumor ovarian stromal cells expressed very low levels of YAP. YAP was also expressed in cultured primary human granulosa cells and in KGN and COV434 GCT cell lines. siRNA-mediated knockdown of YAP in KGN cells resulted in a significant reduction in cell proliferation (P!0.001). Conversely, overexpression of wild type YAP or a constitutively active YAP (YAP1) mutant resulted in a significant increase in KGN cell proliferation and migration. Moreover, YAP knockdown reduced FSH-induced aromatase (CYP19A1) protein expression and estrogen production in KGN cells. These results demonstrate that YAP plays an important role in the regulation of GCTcell proliferation, migration, and steroidogenesis. Targeting the Hippo/YAP pathway may provide a novel therapeutic approach for GCT. [ABSTRACT FROM AUTHOR]

The Hippo/YAP pathway plays an important role in animal organ size control, which it exerts by regulating tissue proliferation and apoptosis rates as a response to developmental cues, cell contact, and density. With the ever increasing advance in genome sequencing and analysis tools, our understanding of the animal world and its evolution has greatly increased in the recent years. We used bioinformatic tools to study the evolution of the Hippo/YAP pathway focusing on the transcriptional coactivator YAP, which is a pivotal effector of the pathway. The aim was to establish the origin and mode of development of YAP and its pathway in the animal world. Some pathway members can be already identified in single-celled eukaryotes like the yeast that have preceded multicellular animals. Interestingly, we can find most of the components that are present in human in the sea-anemone Nematostella, which belongs to a very basal group of metazoans, the cnidarians. All the major domains of YAP have been conserved between cnidarians and mammals, and YAP can be identified even in the more basal placozoan clade. We show a very high degree of conservation in regions such as the WW and the TEAD-binding domains, TEAD being the major DNA-binding partner of YAP. Remarkably, we found that the location of an intron in the WW1 genomic region has been invariant along an evolutionary span of over 700 My. We have followed the evolutionary changes in YAP and in other main components of the pathway from the first metazoans such as sponges, described the phylogenetic relationships between the YAP genes and indicated where YAP and other components have been secondarily lost. Evidence is provided that YAP and its binding partner TEAD demonstrate strong coevolution. This gives further support for the importance of the TEAD–YAP association. Beyond contributing to an understanding of the evolutionary history of this pathway, we have provided insights into the “birth” of this pathway, its functions and its mode of operation in animals with different body plans, development, and life styles. [ABSTRACT FROM PUBLISHER]

The aim of this study was to elucidate the bioactive components and anti-tumor mechanism of poplar propolis extract obtained from North China (CP) in human hepatocellular carcinoma HepG2 cells in vitro. Cell viability and proliferation were measured by SRB assay and EdU proliferation test kit, respectively. Cell migration was evaluated by scratching test. Reactive oxygen species (ROS) production and mitochondrial membrane potential were investigated with the fluorescent probes, DCHF and JC-1, respectively. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were inspected by measurement kits. Apoptosis was assessed by acridine orange (AO) and Hoechst 33258 staining. Levels of Bax, Bcl-2, caspase 9, caspase 3, PARP, MMP-2, MMP-9, PI3K/p-PI3K, AKT/p-AKT, p38MAPK/p-p38 MAPK, ERK/p-ERK, LATS2, YAP, TAZ and TEAD1 were assessed by western blotting, respectively. The bioactive components of CP inhibiting HepG2 cells were mainly flavonoids, and esters. CP induced HepG2 apoptosis through a mitochondrial-dependent intrinsic pathway with elevated the levels of cleaved PARP, cleaved caspase 3, and Bax and decreased the expressions of Bcl-2 and procaspase 9. It seemed that CP triggered apoptosis by activation of the p38 MAPK and inactivation of p-ERK. More importantly, we found that CP suppressed the Hippo pathway, leading to inactivation of YAP/TAZ and TEAD1 and inhibition of PI3K/AKT signaling molecules. CP exerted excellent anti-proliferation and pro-apoptosis actions in HepG2 cells by inactivation of the loop between the Hippo/YAP and PI3K/AKT pathways, and may be a promising therapy for HCC. • The bioactive components of CP inhibiting HCC were firstly elucidated. • CP inhibiting HCC proliferation was mitochondrial-dependent intrinsic pathway. • Hippo/YAP was firstly reported to involve in the antitumor mechanisms of CP. [ABSTRACT FROM AUTHOR]

To discuss the effect and molecular mechanism of circular RNA circ_0067741 on the occurrence and development of lung adenocarcinoma (LUAD). QRT-PCR was utilized to detect circ_0067741, microRNA-183-5p (miR-183-5p) and large tumor suppressor 1 (LATS1) expressions in tumor tissues of 30 LUAD patients and LUAD cell lines (A549, Calu-3, H1299 and H1975). After overexpression or knockdown of circ_0067741-1 or miR-183-5p in H1299 and A549 cells, respectively, cell proliferation, viability, apoptosis, invasion and migration ability and angiogenesis ability were detected by MTT, cell cloning, flow cytometry, transwell and tube formation assays, respectively. The targeted relationship between miR-183-5p and circ_0067741 or LATS1 was validated using dual-luciferase reporter assay. We found that circ_0067741 expression was notably declined in LUAD cells and tissues. Overexpression of circ_0067741 inhibited the proliferation, migration, invasion, and angiogenesis of LUAD cells and promoted apoptosis. Moreover, circ_0067741 could sponge miR-183-5p to regulate LATS1 expression and then activate the Hippo/YAP pathway. Downregulation of LATS1 reversed the effects of circ_0067741 on the Hippo/YAP pathway and LUAD cells progression. In conclusion, circ_0067741 sponges miR-183-5p, and regulates LATS1 to activate Hippo/YAP pathway, thereby inhibiting the process of LUAD cells. And the circ_0067741/miR-183-5p/LATS1 axis can be a potential target for early diagnosis and targeted treatment of LUAD.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterised by an inexorable decline in lung function. The development of IPF involves multiple positive feedback loops; and a strong support role of the Hippo/YAP signalling pathway, which is essential for regulating cell proliferation and organ size, in IPF pathogenesis has been unveiled recently in cell and animal models. YAP/TAZ contributes to both pulmonary fibrosis and alveolar regeneration via the conventional Hippo/YAP signalling pathway, G protein-coupled receptor signalling, and mechanotransduction. Selectively inhibiting YAP/TAZ in lung fibroblasts may inhibit fibroblast proliferation and extracellular matrix deposition, while activating YAP/TAZ in alveolar epithelial cells may promote alveolar regeneration. In this review, we explore, for the first time, the bidirectional and cell-specific regulation of the Hippo/YAP pathway in IPF pathogenesis and discuss recent research progress and future prospects of IPF treatment based on Hippo/YAP signalling, thus providing a basis for the development of new therapeutic strategies to alleviate or even reverse IPF. There is a tendency to develop idiopathic pulmonary fibrosis when severe or continuous lung injury exceeds the ability of the lung to repair itself. During this process, the Hippo pathway in fibroblasts is inhibited, YAP/TAZ enters the nucleus, and promotes the proliferation and activation of fibroblasts into myofibroblasts, which secrets a large amount of extracellular matrix. Their proliferation and pathological repair ability are stronger than that of alveolar epithelial cells. However, a potential therapeutic approach for idiopathic pulmonary fibrosis is to selectively promote YAP/TAZ phosphorylation in fibroblasts to prevent their proliferation by trapping YAP/TAZ in cytoplasm, or selectively promote YAP/TAZ entry into the nucleus of alveolar epithelial cells to promote the regeneration of alveoli. [Display omitted] • The pathological process of IPF is irreversible due to multiple positive feedback. • The Hippo/YAP pathway plays a pivotal role in promoting cell proliferation. • Nuclear translocation of YAP/TAZ in fibroblasts can aggravate IPF. • Same condition in alveolar epithelial cells can contribute to re-epithelialisation. • Selective control of YAP/TAZ may help to treat and even reverse IPF. [ABSTRACT FROM AUTHOR]

The Hippo/YAP (yes-associated protein) pathway is an important signaling pathway to control organ development and tissue homeostasis. YAP is a downstream effector of the Hippo pathway and a critical mediator of mechanic stress. Hypertensive nephropathy is characterized with glomerular sclerosis stiffness and renal fibrosis. The present study investigated the role of YAP pathway in angiotensin (Ang) II hypertensive renal injury by using YAP activation inhibitor verteporfin. Ang II increased the protein expression of YAP in renal nucleus fraction, decreased phospho-YAP, and phospho-LATS1/2 (large tumor suppressors 1 and 2) expressions in renal cytoplasmic fraction, suggesting Ang II activation of renal YAP. Ang II significantly increased systolic blood pressure (SBP), proteinuria, glomerular sclerosis, and fibrosis; treatment with verteporfin attenuated Ang II-induced proteinuria and renal injury with a mild reduction in SBP. Moreover, Ang II increased the protein expressions of inflammatory factors including tumor necrosis factor α, interleukin 1β, and monocyte chemoattractant protein-1, and profibrotic factors including transforming growth factor β, phospho-Smad3 and fibronectin. Verteporfin reversed abovementioned Ang II-induced molecule expressions. Our results for the first time demonstrate that the activation of the YAP pathway promotes hypertensive renal inflammation and fibrosis, which may promote hypertensive renal injury. YAP may be a new target for prevention and treatment of hypertensive renal diseases.

Contrasting with fish or amphibian, retinal regeneration from Müller glia is largely limited in mammals. In our quest toward the identification of molecular cues that may boost their stemness potential, we investigated the involvement of the Hippo pathway effector YAP (Yes-associated protein), which is upregulated in Müller cells following retinal injury. Conditional Yap deletion in mouse Müller cells prevents cell-cycle gene upregulation that normally accompanies reactive gliosis upon photoreceptor cell death. We further show that, in Xenopus , a species endowed with efficient regenerative capacity, YAP is required for their injury-dependent proliferative response. In the mouse retina, where Müller cells do not spontaneously proliferate, YAP overactivation is sufficient to induce their reprogramming into highly proliferative cells. Overall, we unravel a pivotal role for YAP in tuning Müller cell proliferative response to injury and highlight a YAP-EGFR (epidermal growth factor receptor) axis by which Müller cells exit their quiescence state, a critical step toward regeneration. • YAP is required for Xenopus Müller glia proliferation in response to injury • YAP is required for mouse Müller glia exit from quiescence upon degeneration • YAP5SA reprograms mouse Müller glia into highly proliferative cells • YAP functionally interacts with EGFR signaling in Müller cells While fish and amphibian Müller cells behave as retinal stem cells upon injury, their regenerative potential is limited in mammals. Hamon et al. show that YAP is required for their cell-cycle re-entry in Xenopus and is sufficient in mouse to awake them from quiescence and trigger their proliferative response. [ABSTRACT FROM AUTHOR]

Skeletal muscle injuries can cause significant change in the ultrastructure and the metabolism of the skeletal muscle cells. Observation of the ultrastructure and measurements of the metabolism biomarkers such as total superoxide dismutase (T-SOD), malondialdehyde (MDA), and creatine kinase (CK) can be used to evaluate the degree of damage in human skeletal muscle injury. Rolling manipulation is the most popular myofascial release technique in Traditional Chinese Medicine. This study aimed to investigate the effects of intermittent pressure imitating rolling manipulation (IPIRM) of Traditional Chinese Medicine on ultrastructure and metabolism in the injured HSKMCs. Methods: In vitro techniques were used to culture HSKMCs, which were injured with high doses of dexamethasone sodium phosphate. Cells were divided into four groups-control normal group (CNG), control injured group (CIG), rolling manipulation group (RMG), and sine pressure group (SPG). RMG and SPG cells were cyclically exposed to 3.0 Kg (6.6 Pounds) of maximum force at a frequency of 2.0 Hz for 10 min in the Flexcell compression system for duration of 3 days continually. The cell ultrastructure, total superoxide dismutase (T-SOD) activity, malondialdehyde (MDA) content, and creatine kinase (CK) activity of the groups were assessed. Conclusion: These results suggest that the mechanical effects of rolling manipulation in TCM could not only improve the recovery of injured skeletal muscle cells by ameliorating organelles arrangement, reducing organelle swelling, and maintaining nuclear membrane integrity, but also ameliorate the functions of cellular metabolism by increasing T-SOD activity and decreasing MDA content and CK activity in injured skeletal muscle. Then the Hippo/Yap signal pathway was detected, and the proteins in each group were detected by Western Blot. The protein expression of upstream protein p-LATS1 and downstream protein p-Yap (Ser127) in each group was observed to explore the biomechanical mechanism of the method. The relative protein expression of p-LATS1 and p-Yap in (RMG) group was significantly higher than that in injured (CIG) group (P < 0.05). It was suggested that Hippo/Yap pathway was related to the stimulation of 3D human skeletal muscle cells, and the proliferation pathway of 3D human skeletal muscle cells could be opened by stimulation of three dimensional human skeletal muscle cells. It may be one of the biological mechanisms caused by the mechanical effects of manipulations in TCM., Competing Interests: None., (AJTR Copyright © 2020.)

Kyphoplasty is a novel approach treating osteoporotic vertebral compression fractures and poly(methyl methacrylate) (PMMA) is the most common bone cement used for kyphoplasty. Cement leaked into an intervertebral disc (IVD) usually causes problems. Herein, we explored the effects of PMMA particles on the biological behavior of nucleus pulposus cells and proved the inhibiting effect of PMMA particles in a dose-dependent manner. Besides, PMMA particles led to cell cycle arrest and the abnormal expression of several apoptosis associated gene. Futhermore, we found PMMA particles upregulated the expression of p-Mst1/2, p-Lats1, and p-YAP, whereas they downregulated the expression of YAP and CTGF, suggesting the activing effect on the Hippo/YAP/CTGF signaling pathway. By overexpression of YAP, PMMA-induced nucleus pulposus cell degeneration was reversed. In vivo study also showed that recombinant CTGF protein could alleviate PMMA-induced IVD degeneration in rats. To sum up, our study revealed the role of PMMA particles in inducing IVD degeneration by downregulating CTGF through Hippo/YAP pathway.