TY  - JOUR
AU  - Daniel, SG
AU  - Russ, AD
AU  - Guthridge, KM
AU  - Raina, AI
AU  - Estes, PS
AU  - Parsons, LM
AU  - Richardson, HE
AU  - Schroeder, JA
AU  - Zarnescu, DC
Y2  - 2020/12/18
Y1  - 2018/01/01
SN  - 2046-6390
UR  - http://hdl.handle.net/11343/255993
AB  - 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.
LA  - English
PB  - COMPANY BIOLOGISTS LTD
T1  - miR-9a mediates the role of Lethal giant larvae as an epithelial growth inhibitor in Drosophila
DO  - 10.1242/bio.027391
IS  - Biology Open
VL  - 7
IS  - 1
OP  - 299956
OP  - 628401
L1  - /bitstream/handle/11343/255993/PMC5829493.pdf?sequence=1&isAllowed=y
ER  -