Regulation of sarcomagenesis by the Piwi proteins and their interacting small RNAs (piRNAs)
Recently levels of HIWI (the human ortholog of Drosophila PIWI) HIWI, have been found to be expressed in sarcomas with higher HIWI levels correlating significantly with worse clinical outcomes. In lower organisms, PIWI family members silence mobile genomic elements (i.e., transposons) and thus help to maintain genomic integrity via regulating the production of a distinct class of small ‘silencing’ RNAs – aptly named Piwi-interacting RNAs or piRNAs. It is currently unclear as to why ‘higher’ levels of a gene that silences mobile genetic elements would correlate with worse clinical outcomes for sarcoma patients. Our studies have revealed that overexpression of HIWI in mesenchymal stem cells (MSCs; connective tissue progenitors) prevents their differentiation and generates sarcomas. Since Piwi works through generation of piRNAs we feel our models create the perfect environment to identify specific piRNAs that mediate the sarcomagenic process. Our working hypothesis is that overexpression of HIWI results in piRNA mediated suppression of genes that are essential to preventing tumorigenesis. The specific aims of this proposal are to (1) assay for the presence of piRNAs in Hiwi-mediated transformed MSCs and correlate their presence to piRNAs in sarcoma tissues; (2) identify target genes that are deregulated via Hiwi-mediated tumorigenicity; and (3) assess the role of HIWI in promoting sarcomagenesis in vivo and responsiveness to piRNA treatment.
Importantly, since Piwi/piRNA cycle is self-perpetuating, any tumorigenic process initiated by Piwi/piRNA may by permanently terminated via the one time (transient) introduction of the appropriate piRNA – and thus holds great promise as a curative cancer therapy.