miR-9a mediates the role of Lethal giant larvae as an epithelial growth inhibitor in Drosophila
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 01, 2017
- Source ID
- 10.1242/bio.027391
Entities
People
- Ammad I. Raina
- Atlantis D. Russ
- Daniela C Zarnescu
- Helena E. Richardson
- Joyce A. Schroeder
- Kathryn M. Guthridge
- Linda M. Parsons
- Patricia S. Estes
- Scott G. Daniel
Organizations
- Cancer Council Victoria
- La Trobe University
- Monash University
- National Health and Medical Research Council
- United States Department of Defense
- University of Arizona
- University of Melbourne