Abstract
TMPRSS2-ERG junction oncogene is present in more than 50% of patients with prostate cancer and its expression is frequently associated with poor prognosis. Our aim is to achieve gene knockdown by siRNA TMPRSS2-ERG and then to assess the biological consequences of this inhibition. First, we designed siRNAs against the two TMPRSS2-ERG fusion variants (III and IV), most frequently identified in patients’ biopsies. Two of the five siRNAs tested were found to efficiently inhibit mRNA of both TMPRSS2-ERG variants and to decrease ERG protein expression. Microarray analysis further confirmed ERG inhibition by both siRNAs TMPRSS2-ERG and revealed one common down-regulated gene, ADRA2A, involved in cell proliferation and migration. The siRNA against TMPRSS2-ERG fusion variant IV showed the highest anti-proliferative effects: Significantly decreased cell viability, increased cleaved caspase-3 and inhibited a cluster of anti-apoptotic proteins. To propose a concrete therapeutic approach, siRNA TMPRSS2-ERG IV was conjugated to squalene, which can self-organize as nanoparticles in water. The nanoparticles of siRNA TMPRSS2-ERG-squalene injected intravenously in SCID mice reduced growth of VCaP xenografted tumours, inhibited oncoprotein expression and partially restored differentiation (decrease in Ki67). In conclusion, this study offers a new prospect of treatment for prostate cancer based on siRNA-squalene nanoparticles targeting TMPRSS2-ERG junction oncogene.
Highlights
Prostate cancer (PCa), an androgen-dependent tumour, has become the most frequent cancer in men (27% of all cancers in men) and represents the 4th cause of mortality by cancer and the 2nd in men
TMPRSS2-ERG junction oncogene is present in more than 50% of patients with prostate cancer and its expression is frequently associated with poor prognosis
Eight designed primers were used to recognize the variants of TMPRSS2-ERG from I to VIII (S1 Table)
Summary
Our aim is to achieve gene knockdown by siRNA TMPRSS2-ERG and to assess the biological consequences of this inhibition. Knowing that a significant percentage of prostate malignancy harbours the TMPRSS2-ERG junction oncogene, our aim is to introduce a new potential therapeutic approach by siRNA targeting TMPRSS2-ERG junction oncogene in patients with prostate cancer. The aim of this study was to conceive a pharmacological approach targeting TMPRSS2-ERG fusion oncogene by therapeutic siRNA
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