A miR-375/YAP axis regulates neuroendocrine differentiation and tumorigenesis in lung carcinoid cells.

Adaptor Proteins, Signal Transducing / genetics Animals Carcinogenesis / genetics Carcinoid Tumor / genetics Cell Differentiation / genetics Cell Proliferation / genetics Exocytosis / genetics Gene Expression Regulation, Neoplastic Gene Knockdown Techniques HEK293 Cells Humans Lung Neoplasms / genetics Mice Mice, Knockout MicroRNAs / genetics Neuroendocrine Cells / pathology Transcription Factors / genetics Xenograft Model Antitumor Assays YAP-Signaling Proteins

Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
17 05 2021
Historique:
received: 16 09 2020
accepted: 30 04 2021
entrez: 18 5 2021
pubmed: 19 5 2021
medline: 3 11 2021
Statut: epublish

Résumé

Lung carcinoids are variably aggressive and mechanistically understudied neuroendocrine neoplasms (NENs). Here, we identified and elucidated the function of a miR-375/yes-associated protein (YAP) axis in lung carcinoid (H727) cells. miR-375 and YAP are respectively high and low expressed in wild-type H727 cells. Following lentiviral CRISPR/Cas9-mediated miR-375 depletion, we identified distinct transcriptomic changes including dramatic YAP upregulation. We also observed a significant decrease in neuroendocrine differentiation and substantial reductions in cell proliferation, transformation, and tumor growth in cell culture and xenograft mouse disease models. Similarly, YAP overexpression resulted in distinct and partially overlapping transcriptomic changes, phenocopying the effects of miR-375 depletion in the same models as above. Transient YAP knockdown in miR-375-depleted cells reversed the effects of miR-375 on neuroendocrine differentiation and cell proliferation. Pathways analysis and confirmatory real-time PCR studies of shared dysregulated target genes indicate that this axis controls neuroendocrine related functions such as neural differentiation, exocytosis, and secretion. Taken together, we provide compelling evidence that a miR-375/YAP axis is a critical mediator of neuroendocrine differentiation and tumorigenesis in lung carcinoid cells.

Identifiants

DOI: 10.1038/s41598-021-89855-4 PMID: 34001972 PMC: PMC8129150
pubmed: 34001972
doi: 10.1038/s41598-021-89855-4
pii: 10.1038/s41598-021-89855-4
pmc: PMC8129150
doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0
MIRN375 microRNA, human 0
MicroRNAs 0
Transcription Factors 0
YAP-Signaling Proteins 0
YAP1 protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

10455

Références

Hendifar, A. E., Marchevsky, A. M. & Tuli, R. Neuroendocrine tumors of the lung: Current challenges and advances in the diagnosis and management of well-differentiated disease. J. Thorac. Oncol. 12, 425–436 (2017).
pubmed: 27890494 doi: 10.1016/j.jtho.2016.11.2222
Derks, J. L. et al. New insights into the molecular characteristics of pulmonary carcinoids and large cell neuroendocrine carcinomas, and the impact on their clinical management. J. Thorac. Oncol. 13, 752–766 (2018).
pubmed: 29454048 doi: 10.1016/j.jtho.2018.02.002
Hilal, T. Current understanding and approach to well differentiated lung neuroendocrine tumors: An update on classification and management. Ther. Adv. Med. Oncol. 9, 189–199 (2017).
pubmed: 28344664 doi: 10.1177/1758834016678149
Swarts, D. R. A., Ramaekersa, F. C. S. & Speel, E. J. M. Gene expression profiling of pulmonary neuroendocrine neoplasms: A comprehensive overview. Cancer Treat. Commun. 4, 148–160 (2015).
doi: 10.1016/j.ctrc.2015.09.002
Robelin, P. et al. Characterization, prognosis, and treatment of patients with metastatic lung carcinoid tumors. J. Thorac. Oncol. 14, 993–1002 (2019).
pubmed: 30771520 doi: 10.1016/j.jtho.2019.02.002
Torniai, M. et al. Systemic treatment for lung carcinoids: From bench to bedside. Clin. Transl. Med. 8, 22 (2019).
pubmed: 31273555 pmcid: 6609661 doi: 10.1186/s40169-019-0238-5
Michael, I. P., Saghafinia, S. & Hanahan, D. A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis. Proc. Natl. Acad. Sci. U.S.A. 116, 24184–24195 (2019).
pubmed: 31704767 pmcid: 6883852 doi: 10.1073/pnas.1913307116
Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005).
pubmed: 15944708 doi: 10.1038/nature03702
Peng, Y. & Croce, C. M. The role of MicroRNAs in human cancer. Signal Transduct. Target Ther. 1, 15004 (2016).
pubmed: 29263891 pmcid: 5661652 doi: 10.1038/sigtrans.2015.4
Farazi, T. A., Hoell, J. I., Morozov, P. & Tuschl, T. MicroRNAs in human cancer. Adv. Exp. Med. Biol. 774, 1–20 (2013).
pubmed: 23377965 pmcid: 3704221 doi: 10.1007/978-94-007-5590-1_1
Nanayakkara, J. et al. Characterizing and classifying neuroendocrine neoplasms through microRNA sequencing and data mining. NAR Cancer 2, 009 (2020).
doi: 10.1093/narcan/zcaa009
Wong, J. J. M. et al. Classifying lung neuroendocrine neoplasms through microRNA Sequence Data Mining. Cancers (Basel) 12, 2653 (2020).
doi: 10.3390/cancers12092653
Nishikawa, E. et al. miR-375 is activated by ASH1 and inhibits YAP1 in a lineage-dependent manner in lung cancer. Cancer Res. 71, 6165–6173 (2011).
pubmed: 21856745 doi: 10.1158/0008-5472.CAN-11-1020
Zanconato, F., Cordenonsi, M. & Piccolo, S. YAP/TAZ at the roots of cancer. Cancer Cell 29, 783–803 (2016).
pubmed: 27300434 pmcid: 6186419 doi: 10.1016/j.ccell.2016.05.005
Lo Sardo, F., Strano, S. & Blandino, G. YAP and TAZ in lung cancer: Oncogenic role and clinical targeting. Cancers (Basel) 10, 137 (2018).
doi: 10.3390/cancers10050137
Rozengurt, E., Sinnett-Smith, J. & Eibl, G. Yes-associated protein (YAP) in pancreatic cancer: At the epicenter of a targetable signaling network associated with patient survival. Signal Transduct. Target Ther. 3, 11 (2018).
pubmed: 29682330 pmcid: 5908807 doi: 10.1038/s41392-017-0005-2
Yuan, M. et al. Yes-associated protein (YAP) functions as a tumor suppressor in breast. Cell Death Differ. 15, 1752–1759 (2008).
pubmed: 18617895 doi: 10.1038/cdd.2008.108
Wang, H., Du, Y. C., Zhou, X. J., Liu, H. & Tang, S. C. The dual functions of YAP-1 to promote and inhibit cell growth in human malignancy. Cancer Metastasis Rev. 33, 173–181 (2014).
pubmed: 24346160 doi: 10.1007/s10555-013-9463-3
Zhang, X., Abdelrahman, A., Vollmar, B. & Zechner, D. The ambivalent function of YAP in apoptosis and cancer. Int. J. Mol. Sci. 19, 3770 (2018).
pmcid: 6321280 doi: 10.3390/ijms19123770
Ito, T. et al. Loss of YAP1 defines neuroendocrine differentiation of lung tumors. Cancer Sci. 107, 1527–1538 (2016).
pubmed: 27418196 pmcid: 5084673 doi: 10.1111/cas.13013
Horie, M., Saito, A., Ohshima, M., Suzuki, H. I. & Nagase, T. YAP and TAZ modulate cell phenotype in a subset of small cell lung cancer. Cancer Sci. 107, 1755–1766 (2016).
pubmed: 27627196 pmcid: 5198951 doi: 10.1111/cas.13078
Laddha, S. V. et al. Integrative genomic characterization identifies molecular subtypes of lung carcinoids. Cancer Res. 79, 4339–4347 (2019).
pubmed: 31300474 pmcid: 6733269 doi: 10.1158/0008-5472.CAN-19-0214
Yan, J. W., Lin, J. S. & He, X. X. The emerging role of miR-375 in cancer. Int. J. Cancer 135, 1011–1018 (2014).
pubmed: 24166096 doi: 10.1002/ijc.28563
Bulanova, D. R. et al. Orphan G protein-coupled receptor GPRC5A modulates integrin beta1-mediated epithelial cell adhesion. Cell Adhes. Migr. 11, 434–446 (2017).
doi: 10.1080/19336918.2016.1245264
Tao, Q. et al. Identification of the retinoic acid-inducible Gprc5a as a new lung tumor suppressor gene. J. Natl. Cancer Inst. 99, 1668–1682 (2007).
pubmed: 18000218 doi: 10.1093/jnci/djm208
Zhang, Z., Huang, L., Zhao, W. & Rigas, B. Annexin 1 induced by anti-inflammatory drugs binds to NF-kappaB and inhibits its activation: Anticancer effects in vitro and in vivo. Cancer Res. 70, 2379–2388 (2010).
pubmed: 20215502 pmcid: 2953961 doi: 10.1158/0008-5472.CAN-09-4204
Xu, B. et al. Cited2 is required for fetal lung maturation. Dev. Biol. 317, 95–105 (2008).
pubmed: 18358466 pmcid: 2467387 doi: 10.1016/j.ydbio.2008.02.019
Osada, H. et al. Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer. Cancer Res. 68, 1647–1655 (2008).
pubmed: 18339843 doi: 10.1158/0008-5472.CAN-07-5039
Castro, D. S. et al. A novel function of the proneural factor Ascl1 in progenitor proliferation identified by genome-wide characterization of its targets. Genes Dev. 25, 930–945 (2011).
pubmed: 21536733 pmcid: 3084027 doi: 10.1101/gad.627811
Neptune, E. R. et al. Targeted disruption of NeuroD, a proneural basic helix-loop-helix factor, impairs distal lung formation and neuroendocrine morphology in the neonatal lung. J. Biol. Chem. 283, 21160–21169 (2008).
pubmed: 18339630 pmcid: 2475704 doi: 10.1074/jbc.M708692200
Borromeo, M. D. et al. ASCL1 and NEUROD1 reveal heterogeneity in pulmonary neuroendocrine tumors and regulate distinct genetic programs. Cell Rep. 16, 1259–1272 (2016).
pubmed: 27452466 pmcid: 4972690 doi: 10.1016/j.celrep.2016.06.081
Fujino, K. et al. Insulinoma-associated protein 1 is a crucial regulator of neuroendocrine differentiation in lung cancer. Am. J. Pathol. 185, 3164–3177 (2015).
pubmed: 26482608 doi: 10.1016/j.ajpath.2015.08.018
Osipovich, A. B. et al. Insm1 promotes endocrine cell differentiation by modulating the expression of a network of genes that includes Neurog3 and Ripply3. Development 141, 2939–2949 (2014).
pubmed: 25053427 pmcid: 4197673 doi: 10.1242/dev.104810
Zhang, T., Liu, W. D., Saunee, N. A., Breslin, M. B. & Lan, M. S. Zinc finger transcription factor INSM1 interrupts cyclin D1 and CDK4 binding and induces cell cycle arrest. J. Biol. Chem. 284, 5574–5581 (2009).
pubmed: 19124461 pmcid: 2645817 doi: 10.1074/jbc.M808843200
Yu, S. J. et al. MicroRNA-200a promotes anoikis resistance and metastasis by targeting YAP1 in human breast cancer. Clin. Cancer Res. 19, 1389–1399 (2013).
pubmed: 23340296 doi: 10.1158/1078-0432.CCR-12-1959
Kim, E. et al. O-GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity. Proc. Natl. Acad. Sci. 117, 14259–14269 (2020).
pubmed: 32513743 pmcid: 7322088 doi: 10.1073/pnas.1913469117
Janse van Rensburg, H. J. et al. The Hippo pathway component TAZ promotes immune evasion in human cancer through PD-L1. Cancer Res. 78, 1457–1470 (2018).
pubmed: 29339539 doi: 10.1158/0008-5472.CAN-17-3139
Farazi, T. A. et al. Bioinformatic analysis of barcoded cDNA libraries for small RNA profiling by next-generation sequencing. Methods 58, 171–187 (2012).
pubmed: 22836126 pmcid: 3597438 doi: 10.1016/j.ymeth.2012.07.020
Hafner, M. et al. Barcoded cDNA library preparation for small RNA profiling by next-generation sequencing. Methods 58, 164–170 (2012).
pubmed: 22885844 pmcid: 3508525 doi: 10.1016/j.ymeth.2012.07.030
Andrews, S. FASTQC. A quality control tool for high throughput sequence data. Available online at http://www.bioinformatics.babraham.ac.uk/projects/fastqc (2010).
Bolger, A. M., Lohse, M. & Usadel, B. Trimmomatic: A flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120 (2014).
pubmed: 24695404 pmcid: 4103590 doi: 10.1093/bioinformatics/btu170
Bray, N. L., Pimentel, H., Melsted, P. & Pachter, L. Near-optimal probabilistic RNA-seq quantification. Nat. Biotechnol. 34, 525–527 (2016).
doi: 10.1038/nbt.3519 pubmed: 27043002
Panarelli, N. et al. Evaluating gastroenteropancreatic neuroendocrine tumors through microRNA sequencing. Endocr. Relat. Cancer 26, 47–57 (2019).
pubmed: 30021866 doi: 10.1530/ERC-18-0244
Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25, 402–408 (2001).
doi: 10.1006/meth.2001.1262 pubmed: 11846609
Yu, J. et al. TAZ induces lung cancer stem cell properties and tumorigenesis by up-regulating ALDH1A1. Oncotarget 8, 38426–38443 (2017).
pubmed: 28415606 pmcid: 5503543 doi: 10.18632/oncotarget.16430
Nicol, C. J. et al. PPARγ influences susceptibility to DMBA-induced mammary, ovarian and skin carcinogenesis. Carcinogenesis 25, 1747–1755 (2004).
pubmed: 15073042 doi: 10.1093/carcin/bgh160
Raudvere, U. et al. g:Profiler: A web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res. 47, W191–W198 (2019).
pubmed: 31066453 pmcid: 6602461 doi: 10.1093/nar/gkz369
Ashburner, M. et al. Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25–29 (2000).
pubmed: 10802651 pmcid: 3037419 doi: 10.1038/75556
The Gene Ontology Consortium. The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Res. 47, D330–D338 (2019).
doi: 10.1093/nar/gky1055
Fabregat, A. et al. The reactome pathway knowledgebase. Nucleic Acids Res. 46, D649–D655 (2018).
pubmed: 29145629 doi: 10.1093/nar/gkx1132
Shannon, P. et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498–2504 (2003).
pubmed: 14597658 pmcid: 403769 doi: 10.1101/gr.1239303
Merico, D., Isserlin, R., Stueker, O., Emili, A. & Bader, G. D. Enrichment map: A network-based method for gene-set enrichment visualization and interpretation. PLoS ONE 5, e13984 (2010).
pubmed: 21085593 pmcid: 2981572 doi: 10.1371/journal.pone.0013984
Kucera, M., Isserlin, R., Arkhangorodsky, A. & Bader, G. D. AutoAnnotate: A Cytoscape app for summarizing networks with semantic annotations. F1000Res 5, 1717 (2016).
pubmed: 27830058 pmcid: 5082607 doi: 10.12688/f1000research.9090.1

Auteurs

Xiaojing Yang (X)

Laboratory of Translational RNA Biology, Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart St, Kingston, ON, K7L 3N6, Canada.

Jina Nanayakkara (J)

Laboratory of Translational RNA Biology, Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart St, Kingston, ON, K7L 3N6, Canada.

Duncan Claypool (D)

Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, 50 South Drive, Bethesda, MD, 20892, USA.

Sadegh Saghafinia (S)

Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland.

Justin J M Wong (JJM)

Laboratory of Translational RNA Biology, Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart St, Kingston, ON, K7L 3N6, Canada.

Minqi Xu (M)

Laboratory of Translational RNA Biology, Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart St, Kingston, ON, K7L 3N6, Canada.

Xiantao Wang (X)

Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, 50 South Drive, Bethesda, MD, 20892, USA.

Christopher J B Nicol (CJB)

Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart St, Kingston, ON, K7L 3N6, Canada.
Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, 10 Stuart St, Kingston, ON, K7L 3N6, Canada.

Iacovos P Michael (IP)

Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland.

Markus Hafner (M)

Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, 50 South Drive, Bethesda, MD, 20892, USA.

Xiaolong Yang (X)

Cancer Research Laboratory, Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart St, Kingston, ON, K7L 3N6, Canada.

Neil Renwick (N)

Laboratory of Translational RNA Biology, Department of Pathology and Molecular Medicine, Queen's University, 88 Stuart St, Kingston, ON, K7L 3N6, Canada. neil.renwick@queensu.ca.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Eucaryotes › Animaux › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Carcinogenèse › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroendocrines › Tumeur carcinoïde › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Différenciation cellulaire › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Exocytose › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Ciblage de gène › Techniques de knock-down de gènes › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › microARN › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Cellules › Cellules endocrines › Cellules neuroendocrines › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › A miR-375/YAP axis regulates neuroendocrine...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Protéines de signalisation YAP › A miR-375/YAP axis regulates neuroendocrine...