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

摘要

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 thatlglis 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 inDrosophila lglmutants. Among these are several miRNAs previously linked to human cancers includingmiR-9a, which we found to be downregulated inlglneuroepithelial tissues. To determine whethermiR-9acan act as an effector of Lglin vivo, we overexpressed it in the context oflglknock-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 inlglmutant tissues and human breast cancer cells identifiedthrombospondin(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 thatmiR-9amediates Lgl's role in restricting epithelial proliferation, and provides novel insights into pathways controlled by Lgl during tumor progression.