In two different Drosophila models of cancer assayed at the larval stage (see FBhh0000779 and FBhh0000772), it has been observed that tumorigenic cells are transformed into nontumorigenic cells after metamorphosis, and are eventually evicted from adult tissues. It has been shown that this process is dependent upon the increased ecdysone signalling that normally occurs during metamorphosis and into adulthood, and is mediated by the ecdysone-responsive microRNA mir-let7 and its target transcription factor gene chinmo. In these systems, reduction in the levels of either mir-let7 or chinmo results in persistence of tumorigenic cells and metastatic tumor growth in adults.
The human let7 microRNA family has been described as serving tumor suppressor functions, with downregulation observed in various cancers. There are at least 10 members of this family in human; several are encoded by multiple genes. There are also multiple microRNA genes in Drosophila categorized as within this family (as defined by shared 5' seed sequences).
Ecdysone (20-hydroxyecdysone) is the major steroid hormone in insects and plays essential roles in coordinating developmental transitions such as larval molting and metamorphosis; it is a member of a more general class called ecdysteroids. In Drosophila, ecdysone-regulated genes are bound by a heterodimer of ecdysone receptor (encoded by EcR) and Ultraspiracle (encoded by usp). In animals carrying a dominant-negative form of EcR, larval-derived tumorigenic cells continue to grow in adults and result in the accumulation of large tumors throughout the body; similar results are obtained in animals with RNAi-effected knockdown of usp.
[updated Dec. 2018 by FlyBase; FBrf0222196]
In human, 10 members of the let-7 family have been identified (Thammaiah and Jayaram, 2016 pubmed:30159414).
The expression of let-7 family is required for developmental timing and tumor suppressor function; it must be suppressed for the self-renewal of stem cells (Lee et al., 2016; pubmed:26399619).
In various types of human cancer, downregulation of let-7 has been observed (Thammaiah and Jayaram, 2016 pubmed:30159414).
Higher animals have multiple isoforms of let-7 miRNAs encoded by multiple genes within the let-7 miRNA family; these isoforms share a consensus sequence called the 'seed sequence' (Lee et al., 2016; pubmed:26399619).
Low- to moderate-scoring ortholog of human NR1H2, NR1H3, NR1H4 (1 Drosophila to 3 human). Dmel\EcR shares 33-38% identity and 47-55% similarity with the human genes.
Encodes several isoforms of a BTB-zinc finger transcription factor with low levels of homology to several human ZBTB genes.
5' seed sequence homologous to that of human let-7 microRNAs; several other Drosophila miRNAs have 5' seed sequence homologous to human let-7's, including mir-963, mir-977 and mir-984 (FBrf0242402).