Apoptosis induced by a HIPK2 full-length-specific siRNA is due to off-target effects rather than prevalence of HIPK2-Δe8 isoform.

Giorgio Stassi, Matilde Todaro, Giuliana Di Rocco, Veronica Gatti, Ilaria Virdia, Gabriele Toietta, Alessandra Verdina, Silvia Soddu

Risultato della ricerca: Article

4 Citazioni (Scopus)

Abstract

Small interfering RNAs (siRNAs) are widely used to study gene function and extensively exploited for their potential therapeutic applications. HIPK2 is an evolutionary conserved kinase that binds and phosphorylates several proteins directly or indirectly related to apoptosis. Recently, an alternatively spliced isoform skipping 81 nucleotides of exon 8 (Hipk2-∆e8) has been described. Selective depletion of Hipk2 full-length (Hipk2-FL) with a speci c siRNA that spares the Hipk2-∆e8 isoform has been shown to strongly induce apoptosis, suggesting an unpredicted dominant- negative effect of Hipk2-FL over the ∆e8 isoform. From this observation, we sought to take advantage and assessed the therapeutic potential of generating Hipk2 isoform unbalance in tumor-initiating cells derived from colorectal cancer patients. Strong reduction of cell viability was induced in vitro and in vivo by the originally described exon 8-speci c siRNA, supporting a potential therapeutic application. However, validation analyses performed with additional exon8-speci c siRNAs with different stabilities showed that all exon8-targeting siRNAs can induce comparable Hipk2 isoform unbalance but only the originally reported e8-siRNA promotes cell death. These data show that loss of viability does not depend on the prevalence of Hipk2- ∆e8 isoform but it is rather due to microRNA-like off-target effects.
Lingua originaleEnglish
pagine (da-a)1675-1686
Numero di pagine12
RivistaOncotarget
Volume7
Stato di pubblicazionePublished - 2016

All Science Journal Classification (ASJC) codes

  • Oncology

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