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

• Main Authors: 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.
• Other Authors: Univ Arizona, Dept Mol & Cellular Biol
• Language: en
• Published: COMPANY OF BIOLOGISTS LTD 2018
• Subjects: miRNA; Epithelial growth; Drosophila
• Online Access: http://hdl.handle.net/10150/627079; http://arizona.openrepository.com/arizona/handle/10150/627079

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.