Much of the work in flies investigating the role of the Notch pathway in development of cancer has involved combining Notch signaling dysregulation with other genes postulated to have a role in tumorigenesis. This is typically achieved by using targeted expression of an activated form of Notch (N) or overexpression of one of the Notch ligands, Delta (Dl) or Serrate (Ser); see the human disease model report 'cancer, multiple, Notch signaling pathway' (FBhh0000766).
Overexpression of Dl in the adult eye results in a mild overgrowth phenotype; mutations of interacting genes have been identified that enhance this phenotype and result in much increased, tumorous overgrowth. In one such screen, assessing genes in a gain-of-expression system, the microRNA mir-7 was identified; Dmel\mir-7 is orthologous to human microRNAs MIR7-1 MIR7-2, MIR7-3. Knockdowns of predicted mir-7 target genes were then tested in the same assay; of the 39 genes tested, only downregulation ihog via RNAi fully mimicked the effect of mir-7 overexpression, i.e., the transformation of Dl-induced mild overgrowth into severe overgrowth or tumor-like growth.
Since ihog is a core component of the Hedgehog Signaling Pathway (FBgg0000979), other members of this pathway were tested. Tumorigenesis was induced co-operatively following Notch activation (via Dl overexpression) combined with reduced Hedgehog signalling effected by different mechanisms: overexpression of the mir-7 microRNA; or down-regulation of ihog, hh, smo, or ci; or overexpression of the ci repressor form.
See also the human disease model report 'basal cell carcinoma, SMO-related' (FBhh0001201).
[updated Feb. 2020 by FlyBase; FBrf0222196]
Moderate- to high-scoring ortholog of human DLL1 and DLL4 (1 Drosophila to 2 human); additional less closely related genes in human.
High-scoring ortholog of human SHH, DHH, and IHH (3 human to 1 Drosophila).
High-scoring ortholog of human SMO (1 human to 1 Drosophila).
High-scoring ortholog of human GLI3 and GLI2; moderate-scoring ortholog of GLI1 (3 human to 1 Drosophila).