Angiomotin to regulate prostate cancer cell proliferation by signaling through Hippo-YAP pathway.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. e559-e559
Author(s):  
Pengfei Shen ◽  
Hao Zeng ◽  
Angelica Ortiz ◽  
Chien-Jui Cheng ◽  
Yu-Chen Lee ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Neurofibromatosis Type ◽  
Tumor Promoter ◽  
Migration And Invasion ◽  
Junctional Complex ◽  
Chi Square ◽  
Apical Junctional Complex

e559 Background: Angiomotin (AMOT) is a family of proteins found to be a component of the apical junctional complex of vertebrate epithelial cells and is recently found to play important roles in neurofibromatosis type 2 (NF-2). Whether AMOT plays a role in prostate cancer (PCa) is unknown. Methods: Purified GST-AMOTp80 was used as immunogen for antibody generation. Real-time PCR, western blot and immunohistochemistry were used to identify the expression of AMOT. To study the function of AMOT, retroviral vector were constructed, also shRNA was used to knockdown AMOT in cells. Cell migration and invasion assays were performed by using transwell chambers. Nuclear and cytoplasmic protein fractions were prepared by using NE-PER reagents (Pierce). The SPSS 19.0 software was used for statistical analysis. Chi-square test and t test were used for the comparisons between groups. Results: AMOT is expressed as two isoforms, AMOTp80 and AMOTp130, which has a 409 aa N-terminal domain that is absent in AMOTp80. Both AMOTp80 and AMOTp130 are expressed in LNCaP and C4-2B4, but at a low to undetectable level in PC3 cells. Further study showed that AMOTp130 and AMOTp80 have distinct functions in PCa cells. We found that AMOTp80 functioned as a tumor promoter by enhancing PCa cell proliferation while AMOTp130 did not. Mechanistic studies showed that AMOTp80 signaled through the Hippo pathway by promoting the nuclear translocation of YAP, resulting in an increased expression of YAP target protein BMP4. Moreover, inhibition of BMP receptor activity by LDN-193189 abrogates AMOTp80-mediated cell proliferation. Conclusions: Together, this study reveals a novel mechanism whereby the AMOTp80-Merlin-MST1-LATS-YAP-BMP4 pathway leads to AMOTp80-induced tumor cell proliferation.

scholarly journals ZO-2 Is a Master Regulator of Gene Expression, Cell Proliferation, Cytoarchitecture, and Cell Size

2019 ◽  
Vol 20 (17) ◽  
pp. 4128 ◽  
Author(s):  
Lorenza González-Mariscal ◽  
Helios Gallego-Gutiérrez ◽  
Laura González-González ◽  
Christian Hernández-Guzmán
Keyword(s):  
Cell Proliferation ◽  
Cultured Cells ◽  
Hippo Pathway ◽  
Junctional Complex ◽  
Rho Proteins ◽  
Downstream Signaling ◽  
Calcium Sensing ◽  
Apical Junctional Complex ◽  
Regulator Protein ◽  
The Hippo Pathway

ZO-2 is a cytoplasmic protein of tight junctions (TJs). Here, we describe ZO-2 involvement in the formation of the apical junctional complex during early development and in TJ biogenesis in epithelial cultured cells. ZO-2 acts as a scaffold for the polymerization of claudins at TJs and plays a unique role in the blood–testis barrier, as well as at TJs of the human liver and the inner ear. ZO-2 movement between the cytoplasm and nucleus is regulated by nuclear localization and exportation signals and post-translation modifications, while ZO-2 arrival at the cell border is triggered by activation of calcium sensing receptors and corresponding downstream signaling. Depending on its location, ZO-2 associates with junctional proteins and the actomyosin cytoskeleton or a variety of nuclear proteins, playing a role as a transcriptional repressor that leads to inhibition of cell proliferation and transformation. ZO-2 regulates cell architecture through modulation of Rho proteins and its absence induces hypertrophy due to inactivation of the Hippo pathway and activation of mTOR and S6K. The interaction of ZO-2 with viral oncoproteins and kinases and its silencing in diverse carcinomas reinforce the view of ZO-2 as a tumor regulator protein.

scholarly journals Targeting the Hippo Pathway in Prostate Cancer: What’s New?

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 611
Author(s):  
Kelly Coffey
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Hippo Pathway ◽  
Effector Proteins ◽  
Migration And Invasion ◽  
Cell Contact ◽  
Cellular Localisation ◽  
Kinase Cascade ◽  
The Hippo Pathway ◽  
Emergence Of Resistance

Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated for targeting the Hippo signalling pathway. Discovered in Drosophila melanogasta, the Hippo pathway plays a role in the regulation of organ size, proliferation, migration and invasion. In response to a variety of stimuli, including cell–cell contact, nutrients and stress, a kinase cascade is activated, which includes STK4/3 and LATS1/2 to inhibit the effector proteins YAP and its paralogue TAZ. Transcription by their partner transcription factors is inhibited by modulation of YAP/TAZ cellular localisation and protein turnover. Trnascriptional enhanced associate domain (TEAD) transcription factors are their classical transcriptional partner but other transcription factors, including the AR, have been shown to be modulated by YAP/TAZ. In PC, this pathway can be dysregulated by a number of mechanisms, making it attractive for therapeutic intervention. This review looks at each component of the pathway with a focus on findings from the last year and discusses what knowledge can be applied to the field of PC.

scholarly journals The value of miR-510 in the prognosis and development of colon cancer

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 795-804
Author(s):  
Junjie Hang ◽  
Feifei Wei ◽  
Zhiying Yan ◽  
Xianming Zhang ◽  
Kequn Xu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cell Proliferation ◽  
Cultured Cells ◽  
Malignant Tumors ◽  
Prognostic Indicator ◽  
Tumor Promoter ◽  
Migration And Invasion ◽  
Clinical Prognosis ◽  
Normal Tissues ◽  
Novel Therapeutic Strategies

Abstract Purpose Colon cancer is one of the malignant tumors that threatens human health. miR-510 was demonstrated to play roles in the progression of various cancers; its dysregulation was speculated to be associated with the development of colon cancer. Methods One hundred and thirteen colon cancer patients participated in this research. With the help of RT-qPCR, the expression of miR-510 in collected tissues and cultured cells was analyzed. The association between miR-510 expression level and clinical features and prognosis of patients was evaluated. Moreover, the effects of miR-510 on cell proliferation, migration, and invasion of colon cancer were assessed by CCK8 and Transwell assay. Results miR-510 significantly upregulated in colon cancer tissues and cell lines relative to the adjacent normal tissues and colonic cells. The expression of miR-510 was significantly associated with the TNM stage and poor prognosis of patients, indicating miR-510 was involved in the disease progression and clinical prognosis of colon cancer. Additionally, the upregulation of miR-510 significantly promoted cell proliferation, migration, and invasion of colon cancer, while its knockdown significantly inhibited these cellular processes. SRCIN 1 was the direct target of miR-510 during its promoted effect on the development of colon cancer. Conclusion The upregulation of miR-510 acts as an independent prognostic indicator and a tumor promoter by targeting SRCIN 1 in colon cancer, which provides novel therapeutic strategies for colon cancer.

scholarly journals Biomarker potential of lncRNA GNAS-AS1 in osteosarcoma prognosis and effect on cellular function

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Zhanhu Mi ◽  
Yanyun Dong ◽  
Zhibiao Wang ◽  
Peng Ye
Keyword(s):  
Cell Proliferation ◽  
Cell Function ◽  
Cox Regression ◽  
Bone Cancer ◽  
Prognostic Indicator ◽  
Migration And Invasion ◽  
Rank Test ◽  
Chi Square ◽  
Invasion And Migration ◽  
Novel Therapeutic Strategies

Abstract Background Osteosarcoma (OS) is a type of bone cancer that occurs in children and adolescents at a rate of 5%. The purpose of this study is to explore the lncRNA GNAS-AS1 expression profile, prognosis significance in OS, and biological effect on OS cell function. Methods One hundred eight pairs of tissues were collected, and OS cell lines were purchased. lncRNA GNAS-AS1 expression in these tissues and cells were analyzed by qRT-PCR. Clinical data were analyzed using chi-square tests, Kaplan-Meier curves (log-rank test), and Cox regression. CCK-8 and transwell assay were conducted to analyze the effect of lncRNA GNAS-AS1 on cell proliferation, invasion, and migration. The downstream miRNA was presumed. Results The expression of lncRNA GNAS-AS1 was significantly increased in OS cells and tissues, and related to Enneking staging and distant metastasis. Patients with high lncRNA GNAS-AS1 expression represented shorter overall survival and was an independent prognostic predictor of OS. LncRNA GNAS-AS1 knockdown inhibited cell proliferation, migration, and invasion by regulated miR-490-3p partly at least. Conclusions LncRNA GNAS-AS1 can be used as a prognostic indicator and its inhibition suppress the development of OS, suggesting its value as novel therapeutic strategies in OS.

scholarly journals NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway

2011 ◽  
Vol 193 (4) ◽  
pp. 633-642 ◽  
Author(s):  
Sandra Habbig ◽  
Malte P. Bartram ◽  
Roman U. Müller ◽  
Ricarda Schwarz ◽  
Nikolaos Andriopoulos ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Negative Regulator ◽  
Hippo Signaling ◽  
Transcriptional Coactivator ◽  
Hippo Signaling Pathway ◽  
The Hippo Pathway ◽  
Potent Negative Regulator

The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.

MiR-375 Enriched in Bone Marrow Mesenchymal Stem Cells (BMSC) Exosomes Inhibits Prostate Cancer Cell Migration and Invasion by Down-Regulating Trefoil Factor 3 (TFF3)

2021 ◽  
Vol 11 (12) ◽  
pp. 2407-2414
Author(s):  
Qihong Liang ◽  
Wei Zhong
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Cell Proliferation ◽  
Cell Migration ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Clinical Samples ◽  
Cell Migration And Invasion ◽  
Marrow Mesenchymal Stem Cells ◽  
Proliferation And Metastasis

To study the effect and mechanism of miR-375 enriched in BMSC exosomes on prostate cancer (PC) cells. Bioinformatics assessed the potential regulatory miRNA of TFF3 and miR-375 level in breast cancer cells and breast cancer clinical samples was detected by PCR. Dual luciferase assay validated the relationship between TFF3 and miR-375. miR-375 mimics or sh-TFF3 was transfected into PC cells, followed by measuring miR-375 and TFF3 by PCR and Western-blot. Cell proliferation, invasion, migration and apoptosis by Edu staining, transwell and flow cytometry. The BMSC exosomes were then isolated and co-cultured with PC cells to detect cell proliferation and invasion. PC cells and tissues showed the expression of miR-375 was decreased, indicated that miR-375 specifically inhibited TFF3 level. miR-375 was enriched in MSC-derived exosomes and could be transferred to PC cells. miR-375 mimics, exosome miR-375 or silenced TFF3 inhibited TFF3 level, up-regulated PCNA, MMP-2/9 expression, thereby inhibiting cell proliferation and metastasis, and promoting cell apoptosis. miR-375 is enriched in BMSC exosomes and inhibits PC cell migration and invasion by reducing TFF3.

scholarly journals LINC00908 negatively regulates microRNA-483-5p to increase TSPYL5 expression and inhibit the development of prostate cancer

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Li Fan ◽  
Hai Li ◽  
Yun Zhang
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Rna Binding ◽  
Quantitative Polymerase Chain Reaction ◽  
Gene Expression Omnibus ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
In Vivo Experiments

Abstract Background Accumulating evidence has associated aberrant long non-coding RNAs (lncRNAs) with various human cancers. This study aimed to explore the role of LINC00908 in prostate cancer (PCa) and its possible underlying mechanisms. Methods Microarray data associated with PCa were obtained from the Gene Expression Omnibus (GEO) to screen the differentially expressed genes or lncRNAs. Then, the expression of LINC00908 in PCa tissues and cell lines was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The localization of LINC00908 in PCa cells was examined by fluorescence in situ hybridization (FISH). The relationship among LINC00908, microRNA (miR)-483-5p, and TSPYL5 was detected by bioinformatics analysis, dual-luciferase reporter assay, RNA pull-down, RNA binding protein immunoprecipitation (RIP), and FISH assays. Cell biological behaviors were assessed after the expression of LINC00908, miR-483-5p, and TSPYL5 was altered in PCa cells. Lastly, tumor growth in nude mice was evaluated. Results Poorly expressed LINC00908 was witnessed in PCa tissues and cells. LINC00908 competitively bound to miR-483-5p to up-regulate the TSPYL5 expression. Overexpression of LINC00908 resulted in reduced PCa cell proliferation, migration and invasion, and promoted apoptosis. Additionally, the suppression on PCa cell proliferation, migration and invasion was induced by up-regulation of TSPYL5 or inhibition of miR-483-5p. In addition, in vivo experiments showed that overexpression of LINC00908 inhibited tumor growth of PCa. Conclusion Overall, LINC00908 could competitively bind to miR-483-5p to increase the expression of TSPYL5, thereby inhibiting the progression of PCa. Therefore, LINC00908 may serve as a novel target for the treatment of PCa.

scholarly journals MEIS2C and MEIS2D promote tumor progression via Wnt/β-catenin and hippo/YAP signaling in hepatocellular carcinoma

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Lei Guan ◽  
Ting Li ◽  
Nanping Ai ◽  
Wei Wang ◽  
Bing He ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chromatin Immunoprecipitation ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Therapeutic Strategies ◽  
Regulatory Mechanisms ◽  
Migration And Invasion ◽  
Gene Regulatory

Abstract Background MEIS2 has been identified as one of the key transcription factors in the gene regulatory network in the development and pathogenesis of human cancers. Our study aims to identify the regulatory mechanisms of MEIS2 in hepatocellular carcinoma (HCC), which could be targeted to develop new therapeutic strategies. Methods The variation of MEIS2 levels were assayed in a cohort of HCC patients. The proliferation, clone-formation, migration, and invasion abilities of HCC cells were measured to analyze the effects of MEIS2C and MEIS2D (MEIS2C/D) knockdown with small hairpin RNAs in vitro and in vivo. Chromatin immunoprecipitation (ChIP) was performed to identify MEIS2 binding site. Immunoprecipitation and immunofluorescence assays were employed to detect proteins regulated by MEIS2. Results The expression of MEIS2C/D was increased in the HCC specimens when compared with the adjacent noncancerous liver (ANL) tissues. Moreover, MEIS2C/D expression negatively correlated with the prognosis of HCC patients. On the other hand, knockdown of MEIS2C/D could inhibit proliferation and diminish migration and invasion of hepatoma cells in vitro and in vivo. Mechanistically, MESI2C activated Wnt/β-catenin pathway in cooperation with Parafibromin (CDC73), while MEIS2D suppressed Hippo pathway by promoting YAP nuclear translocation via miR-1307-3p/LATS1 axis. Notably, CDC73 could directly either interact with MEIS2C/β-catenin or MEIS2D/YAP complex, depending on its tyrosine-phosphorylation status. Conclusions Our studies indicate that MEISC/D promote HCC development via Wnt/β-catenin and Hippo/YAP signaling pathways, highlighting the complex molecular network of MEIS2C/D in HCC pathogenesis. These results suggest that MEISC/D may serve as a potential novel therapeutic target for HCC.

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