Cargando…

miR-9a mediates the role of Lethal giant larvae as an epithelial growth inhibitor in Drosophila

Drosophila lethal giant larvae (lgl) encodes a conserved tumor suppressor with established roles in cell polarity, asymmetric division, and proliferation control. Lgl's human orthologs, HUGL1 and HUGL2, are altered in human cancers, however, its mechanistic role as a tumor suppressor remains po...

Descripción completa

Detalles Bibliográficos
Autores principales: Daniel, Scott G., Russ, Atlantis D., Guthridge, Kathryn M., Raina, Ammad I., Estes, Patricia S., Parsons, Linda M., Richardson, Helena E., Schroeder, Joyce A., Zarnescu, Daniela C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829493/
https://www.ncbi.nlm.nih.gov/pubmed/29361610
http://dx.doi.org/10.1242/bio.027391
_version_ 1783302815256412160
author Daniel, Scott G.
Russ, Atlantis D.
Guthridge, Kathryn M.
Raina, Ammad I.
Estes, Patricia S.
Parsons, Linda M.
Richardson, Helena E.
Schroeder, Joyce A.
Zarnescu, Daniela C.
author_facet Daniel, Scott G.
Russ, Atlantis D.
Guthridge, Kathryn M.
Raina, Ammad I.
Estes, Patricia S.
Parsons, Linda M.
Richardson, Helena E.
Schroeder, Joyce A.
Zarnescu, Daniela C.
author_sort Daniel, Scott G.
collection PubMed
description Drosophila lethal giant larvae (lgl) encodes a conserved tumor suppressor with established roles in cell polarity, asymmetric division, and proliferation control. Lgl's human orthologs, HUGL1 and HUGL2, are altered in human cancers, however, its mechanistic role as a tumor suppressor remains poorly understood. Based on a previously established connection between Lgl and Fragile X protein (FMRP), a miRNA-associated translational regulator, we hypothesized that Lgl may exert its role as a tumor suppressor by interacting with the miRNA pathway. Consistent with this model, we found that lgl is a dominant modifier of Argonaute1 overexpression in the eye neuroepithelium. Using microarray profiling we identified a core set of ten miRNAs that are altered throughout tumorigenesis in Drosophila lgl mutants. Among these are several miRNAs previously linked to human cancers including miR-9a, which we found to be downregulated in lgl neuroepithelial tissues. To determine whether miR-9a can act as an effector of Lgl in vivo, we overexpressed it in the context of lgl knock-down by RNAi and found it able to reduce the overgrowth phenotype caused by Lgl loss in epithelia. Furthermore, cross-comparisons between miRNA and mRNA profiling in lgl mutant tissues and human breast cancer cells identified thrombospondin (tsp) as a common factor altered in both fly and human breast cancer tumorigenesis models. Our work provides the first evidence of a functional connection between Lgl and the miRNA pathway, demonstrates that miR-9a mediates Lgl's role in restricting epithelial proliferation, and provides novel insights into pathways controlled by Lgl during tumor progression.
format Online
Article
Text
id pubmed-5829493
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher The Company of Biologists Ltd
record_format MEDLINE/PubMed
spelling pubmed-58294932018-02-28 miR-9a mediates the role of Lethal giant larvae as an epithelial growth inhibitor in Drosophila Daniel, Scott G. Russ, Atlantis D. Guthridge, Kathryn M. Raina, Ammad I. Estes, Patricia S. Parsons, Linda M. Richardson, Helena E. Schroeder, Joyce A. Zarnescu, Daniela C. Biol Open Research Article Drosophila lethal giant larvae (lgl) encodes a conserved tumor suppressor with established roles in cell polarity, asymmetric division, and proliferation control. Lgl's human orthologs, HUGL1 and HUGL2, are altered in human cancers, however, its mechanistic role as a tumor suppressor remains poorly understood. Based on a previously established connection between Lgl and Fragile X protein (FMRP), a miRNA-associated translational regulator, we hypothesized that Lgl may exert its role as a tumor suppressor by interacting with the miRNA pathway. Consistent with this model, we found that lgl is a dominant modifier of Argonaute1 overexpression in the eye neuroepithelium. Using microarray profiling we identified a core set of ten miRNAs that are altered throughout tumorigenesis in Drosophila lgl mutants. Among these are several miRNAs previously linked to human cancers including miR-9a, which we found to be downregulated in lgl neuroepithelial tissues. To determine whether miR-9a can act as an effector of Lgl in vivo, we overexpressed it in the context of lgl knock-down by RNAi and found it able to reduce the overgrowth phenotype caused by Lgl loss in epithelia. Furthermore, cross-comparisons between miRNA and mRNA profiling in lgl mutant tissues and human breast cancer cells identified thrombospondin (tsp) as a common factor altered in both fly and human breast cancer tumorigenesis models. Our work provides the first evidence of a functional connection between Lgl and the miRNA pathway, demonstrates that miR-9a mediates Lgl's role in restricting epithelial proliferation, and provides novel insights into pathways controlled by Lgl during tumor progression. The Company of Biologists Ltd 2017-12-20 /pmc/articles/PMC5829493/ /pubmed/29361610 http://dx.doi.org/10.1242/bio.027391 Text en © 2018. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Daniel, Scott G.
Russ, Atlantis D.
Guthridge, Kathryn M.
Raina, Ammad I.
Estes, Patricia S.
Parsons, Linda M.
Richardson, Helena E.
Schroeder, Joyce A.
Zarnescu, Daniela C.
miR-9a mediates the role of Lethal giant larvae as an epithelial growth inhibitor in Drosophila
title miR-9a mediates the role of Lethal giant larvae as an epithelial growth inhibitor in Drosophila
title_full miR-9a mediates the role of Lethal giant larvae as an epithelial growth inhibitor in Drosophila
title_fullStr miR-9a mediates the role of Lethal giant larvae as an epithelial growth inhibitor in Drosophila
title_full_unstemmed miR-9a mediates the role of Lethal giant larvae as an epithelial growth inhibitor in Drosophila
title_short miR-9a mediates the role of Lethal giant larvae as an epithelial growth inhibitor in Drosophila
title_sort mir-9a mediates the role of lethal giant larvae as an epithelial growth inhibitor in drosophila
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829493/
https://www.ncbi.nlm.nih.gov/pubmed/29361610
http://dx.doi.org/10.1242/bio.027391
work_keys_str_mv AT danielscottg mir9amediatestheroleoflethalgiantlarvaeasanepithelialgrowthinhibitorindrosophila
AT russatlantisd mir9amediatestheroleoflethalgiantlarvaeasanepithelialgrowthinhibitorindrosophila
AT guthridgekathrynm mir9amediatestheroleoflethalgiantlarvaeasanepithelialgrowthinhibitorindrosophila
AT rainaammadi mir9amediatestheroleoflethalgiantlarvaeasanepithelialgrowthinhibitorindrosophila
AT estespatricias mir9amediatestheroleoflethalgiantlarvaeasanepithelialgrowthinhibitorindrosophila
AT parsonslindam mir9amediatestheroleoflethalgiantlarvaeasanepithelialgrowthinhibitorindrosophila
AT richardsonhelenae mir9amediatestheroleoflethalgiantlarvaeasanepithelialgrowthinhibitorindrosophila
AT schroederjoycea mir9amediatestheroleoflethalgiantlarvaeasanepithelialgrowthinhibitorindrosophila
AT zarnescudanielac mir9amediatestheroleoflethalgiantlarvaeasanepithelialgrowthinhibitorindrosophila