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Biol Open. 2018 Jan 26;7(1). pii: bio027391. doi: 10.1242/bio.027391.

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

Author information

1
Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA.
2
Genetics Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ 85721, USA.
3
Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA.
4
Cell Cycle and Development Laboratory, Research Division, Peter MacCallum Cancer Center, Melbourne, Victoria 3000, Australia.
5
Department of Genetics, University of Melbourne, Melbourne, Victoria 3010, Australia.
6
Sir Peter MacCallum Department of Oncology, Department of Anatomy & Neuroscience, Department of Biochemistry & Molecular Biology, University of Melbourne, Melbourne, Victoria 3000, Australia.
7
Department of Biochemistry & Genetics, La Trobe Institute of Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
8
Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA zarnescu@email.arizona.edu.

Abstract

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.

KEYWORDS:

Drosophila; Epithelial growth; miRNA

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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