miR-9a mediates the role of Lethal giant larvae as an epithelial growth inhibitor in Drosophila
AuthorDaniel, SG; Russ, AD; Guthridge, KM; Raina, AI; Estes, PS; Parsons, LM; Richardson, HE; Schroeder, JA; Zarnescu, DC
Source TitleBiology Open
PublisherCOMPANY BIOLOGISTS LTD
AffiliationAnatomy and Neuroscience
Document TypeJournal Article
CitationsDaniel, S. G., Russ, A. D., Guthridge, K. M., Raina, A. I., Estes, P. S., Parsons, L. M., Richardson, H. E., Schroeder, J. A. & Zarnescu, D. C. (2018). miR-9a mediates the role of Lethal giant larvae as an epithelial growth inhibitor in Drosophila. BIOLOGY OPEN, 7 (1), https://doi.org/10.1242/bio.027391.
Access StatusOpen Access
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.
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