YAP Activation and Implications in Patients and a Mouse Model of Biliary Atresia

Background and Aim: Biliary atresia (BA), an inflammatory destruction of the bile ducts, leads to liver fibrosis in infants and accounts for half of cases undergoing pediatric liver transplantation. Yes-associated protein (YAP), an effector of the Hippo signaling pathway, is critical in maintaining identities of bile ductal cells. Here, we evaluated the expression of YAP and YAP target genes in BA livers and a rhesus rotavirus (RRV)-induced BA mice model.Methods: Liver specimens collected from 200 BA patients were compared with those of 30 non-BA patients. Model mice liver tissues were also collected. The expression of YAP and YAP target genes were measured by transfection, RNA-seq, immunohistochemistry, immunoblot, and quantitative PCR. Masson's trichrome staining and the Biliary Atresia Research Consortium (BARC) system were utilized to score liver fibrosis status.Results: The expression of YAP is elevated and positively correlated with fibrosis in BA livers. Moreover, ANKRD1, which is identified as the target gene of YAP, is also highly expressed in BA livers. Consistent with clinical data, YAP and ANKRD1 are significantly upregulated in RRV-induced BA mouse model.Conclusions: YAP expression is closely correlated with the bile duct hyperplasia and liver fibrosis, and may serve as an indicator for liver fibrosis and BA progression. This study indicates an involvement of the Hippo signaling pathway in the development of BA, and the YAP induced ANKRD1 expression may also be related to bile duct hyperplasia in BA. This provides a new direction for more in-depth exploration of the etiology and pathogenesis of biliary atresia.

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Inhibition of Hippo Signaling Improves Skin Lesions in a Rosacea-Like Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms22020931 ◽

2021 ◽

Vol 22 (2) ◽

pp. 931

Author(s):

Jihyun Lee ◽

Yujin Jung ◽

Seo won Jeong ◽

Ga Hee Jeong ◽

Gue Tae Moon ◽

...

Keyword(s):

Mouse Model ◽

Signaling Pathway ◽

Normal Skin ◽

Skin Lesions ◽

Hippo Signaling ◽

Vascular Endothelial ◽

Expression Levels ◽

Hippo Signaling Pathway ◽

Endothelial Growth Factor

The Hippo signaling pathway plays a key role in regulating organ size and tissue homeostasis. Hippo and two of its main effectors, yes-associated protein (YAP) and WWTR1 (WW domain-containing transcription regulator 1, commonly listed as TAZ), play critical roles in angiogenesis. This study investigated the role of the Hippo signaling pathway in the pathogenesis of rosacea. We performed immunohistochemical analyses to compare the expression levels of YAP and TAZ between rosacea skin and normal skin in humans. Furthermore, we used a rosacea-like BALB/c mouse model induced by LL-37 injections to determine the roles of YAP and TAZ in rosacea in vivo. We found that the expression levels of YAP and TAZ were upregulated in patients with rosacea. In the rosacea-like mouse model, we observed that the clinical features of rosacea, including telangiectasia and erythema, improved after the injection of a YAP/TAZ inhibitor. Additionally, treatment with a YAP/TAZ inhibitor reduced the expression levels of YAP and TAZ and diminished vascular endothelial growth factor (VEGF) immunoreactivity in the rosacea-like mouse model. Our findings suggest that YAP/TAZ inhibitors can attenuate angiogenesis associated with the pathogenesis of rosacea and that both YAP and TAZ are potential therapeutic targets for patients with rosacea.

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Overexpression of Agrin promotes tumor proliferation and correlates with poor prognosis in cholangiocarcinoma

10.21203/rs.3.rs-50004/v1 ◽

2020 ◽

Author(s):

Meimei He ◽

Shasha Ji ◽

Junxue Tu ◽

Dan Lou

Keyword(s):

Cell Cycle ◽

Signaling Pathway ◽

Cell Lines ◽

Target Genes ◽

Intrahepatic Metastasis ◽

Control Group ◽

Hippo Signaling ◽

Tumor Characteristics ◽

Hippo Signaling Pathway

Abstract Background Agrin exists as a shorter Type II Transmembrane form with an internal signal peptide, and is closely correlated with the activation of multiple intercellular signaling pathways. The aim of the present study was to investigate the role of Agrin in the development of cholangiocarcinoma (CCA). Methods RT-qPCR and western blotting were performed to detect the expressional level of target genes, including Agrin, in CCA tissues or cell lines. The correlation between Agrin, and tumor characteristics and prognosis, was analyzed using independent sample t-test, the Kaplan-Meier method and Cox proportional hazard model, respectively. Proliferation, migration, invasion and tumorigenesis in CCA cells was determined by CCK8 assay, cell cycle detection, Transwell assay and nude mouse tumorigenicity assay, respectively. Results Agrin was significantly upregulated in CCA tissues, as compared to the adjacent non-tumor tissues, and was correlated with poorer tumor characteristics such as portal vein tumor thrombus, intrahepatic metastasis and poor survival. The Agrin overexpression in CCA cell lines clearly promoted proliferation, colony formation, migration, invasion and cell cycle progression, but Agrin knockdown had the opposite effect. Furthermore, CCA cells with inhibitory Agrin expression presented with less and smaller tumors, as compared with the control group in vivo. Mechanistic analysis indicated that Agrin was able to activate the Hippo signaling pathway and induce yap to enter the cell nucleus. Conclusions We found that Agrin promotes the CCA progression via activating the Hippo signaling pathway, which could be a potentially promising target for CCA treatment.

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miR-24-3p Promotes Cell Proliferation, Migration, and Invasion of Human Cervical Cancer Cells through/via Targeting AMOTL2 and Attenuating the YAP/Hippo Pathway

10.21203/rs.3.rs-708235/v1 ◽

2021 ◽

Author(s):

Yiyun Huang ◽

Lijun Hu ◽

Lu Lin ◽

Yan Liu ◽

Yan Zhang ◽

...

Keyword(s):

Cervical Cancer ◽

Cell Proliferation ◽

Cancer Cells ◽

Signaling Pathway ◽

Target Genes ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Cervical Cancer Cells

Abstract BackgroundmiR-24-3p promotes the development of the majority of malignancies.However, its function in cervical cancer is not clearly elucidated so far.MethodsIn this study, cell proliferation, migration, and invasion were measured by the CCK8 and transwell assays. Bioinformatic methods were used to predict the target genes of miR-24-3p, verifying by luciferase reporter assay and western blotting. The target genes set was also used for KEGG pathway enrichment analysis. ResultsThen we obsrved higher miR-24-3p level in cervical cancer cells and faster growth of tumor in a xenograft model. The function assays demonstrated that miR-24-3p promoted proliferation, migration, and invasion of cervical cancer cells in vitro. It was confirmed that miR-24-3p directly targeted AMOTL2 and the recovery of AMOTL2 reversed the function of miR-24-3p in cervical cancer cell line CaSki. Besides, miR-24-3p suppressed the Hippo signaling pathway in CaSki and SiHa cells. ConclusionsIn conclusion, our results reminded that miR-24-3p could boost the migration and proliferation of cervical cancer cells via down-regulating AMOTL2 and attenuating YAP/Hippo signaling pathway activity.

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Therapeutic effects of Chlorella vulgaris on carbon tetrachloride induced liver fibrosis by targeting Hippo signaling pathway and AMPK/FOXO1 axis

Molecular Biology Reports ◽

10.1007/s11033-020-05978-3 ◽

2020 ◽

Author(s):

Roohollah Mohseni ◽

Seyed Moayed Alavian ◽

Zahra Arab Sadeghabadi ◽

Mohammad Heiat

Keyword(s):

Carbon Tetrachloride ◽

Liver Fibrosis ◽

Signaling Pathway ◽

Chlorella Vulgaris ◽

Therapeutic Effects ◽

Hippo Signaling ◽

Hippo Signaling Pathway

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Functional annotation of extensively and divergently expressed miRNAs in suprachiasmatic nucleus of ClockΔ19 mutant mice

Bioscience Reports ◽

10.1042/bsr20180233 ◽

2018 ◽

Vol 38 (6) ◽

Cited By ~ 3

Author(s):

Yanli Wang ◽

Ke Lv ◽

Hailong Chen ◽

Mei Zhao ◽

Guohua Ji ◽

...

Keyword(s):

Circadian Rhythms ◽

Signaling Pathway ◽

Target Genes ◽

Mutant Mice ◽

Hippo Signaling ◽

Time Points ◽

Hippo Signaling Pathway ◽

Mirnas Expression ◽

Phase Amplitude

Circadian locomotor output cycles kaput protein (CLOCK) is a core transcription factor of complex integrated feedback loops in mammalian circadian clock. More genes have been reported to be regulated by CLOCK, however little is known about the role of CLOCK-mediated miRNAs. To dissect this, we used microarray analysis to measure miRNAs expression in suprachiasmatic nuclei (SCN) of wild-type (WT) and ClockΔ19 mutant mice at two different time points. We found that miRNAs regulation in two time points was extensive (nearly 75% of the miRNAs expressed at each time point), and very little overlap, with only six miRNAs in common. Besides this, the predicted CLOCK regulated miRNAs at two time points participated in extremely diverse pathways. We validated nine miRNAs (miR-125a-3p, miR-144, miR-199a-5p, miR-199b*, miR-200a, miR-200b, miR-203, miR-449a, and miR-96), which were involved in the same signaling pathway-hippo signaling pathway. The rhythms of these miRNAs showed a broad distribution of phase, amplitude, and waveform in Clock mutation. And further analysis indicated that there may be three models of miRNA-mediated circadian rhythms and hippo signaling pathway. MiRNA, the small player, may play a hub role in connecting circadian rhythms and other pathways via its multiple target genes networks.

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Hippo signaling pathway in mammals：a new therapeutic target for tumors

Hereditas (Beijing) ◽

10.3724/sp.j.1005.2012.00269 ◽

2012 ◽

Vol 34 (3) ◽

pp. 269-280 ◽

Cited By ~ 2

Author(s):

Chuan-Ming XU ◽

Fu-Sheng WAN

Keyword(s):

Signaling Pathway ◽

Therapeutic Target ◽

Hippo Signaling ◽

Hippo Signaling Pathway

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Hsa_circ_0005273 facilitates breast cancer tumorigenesis by regulating YAP1-hippo signaling pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01830-z ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Xuehui Wang ◽

Changle Ji ◽

Jiashu Hu ◽

Xiaochong Deng ◽

Wenfang Zheng ◽

...

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Cell Lines ◽

Luciferase Reporter ◽

Circular Rnas ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Potential Biomarker

Abstract Background Circular RNAs (circRNAs), a novel class of endogenous RNAs, have shown to participate in the development of breast cancer (BC). Hsa_circ_0005273 is a circRNA generated from several exons of PTK2. However, the potential functional role of hsa_circ_0005273 in BC remains largely unknown. Here we aim to evaluate the role of hsa_circ_0005273 in BC. Methods The expression level of hsa_circ_0005273 and miR-200a-3p were examined by RT-qPCR in BC tissues and cell lines. The effect of knocking down hsa_circ_0005273 in BC cell lines were evaluated by examinations of cell proliferation, migration and cell cycle. In addition, xenografts experiment in nude mice were performed to evaluate the effect of hsa_circ_0005273 in BC. RNA immunoprecipitation assay, RNA probe pull-down assay, luciferase reporter assay and fluorescence in situ hybridization were conducted to confirm the relationship between hsa_circ_0005273, miR-200a-3p and YAP1. Results Hsa_circ_0005273 is over-expressed in BC tissues and cell lines, whereas miR-200a-3p expression is repressed. Depletion of hsa_circ_0005273 inhibited the progression of BC cells in vitro and in vivo, while overexpression of hsa_circ_0005273 exhibited the opposite effect. Importantly, hsa_circ_0005273 upregulated YAP1 expression and inactivated Hippo pathway via sponging miR-200a-3p to promote BC progression. Conclusions Hsa_circ_0005273 regulates the miR-200a-3p/YAP1 axis and inactivates Hippo signaling pathway to promote BC progression, which may become a potential biomarker and therapeutic target.

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