Silencing the leukaemic fusion gene RUNX1/ETO by siRNA-loaded lipid nanoparticles restores myeloid differentiation
Laura E. SwartAnita van OortMinoo AshtianiAnja Krippner‐HeidenreichSander A.A. KooijmansD TukArnold C. KoekmanCornelis SeinenHasan IssaH BlairRM SchiffelersOlaf Heidenreich
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Leukeamias are often driven by the expression of leukaemic-specific fusion genes. Exclusive targeting using RNA interference is therefore an attractive therapeutic concept, but lacks so far suitable delivery systems. Here, we use targeted lipid nanoparticles (LNPs) containing siRNA (siRE) to reduce RUNX1/ETO protein expression in patient-derived AML cells.Relationships of immune genes in adult honeybees (Apis mellifera) were investigated using RNA interference (RNAi). Quantitative RT-PCR was applied to estimate gene expression and the extent of gene silencing. Relish is a transcription factor and forms an important part of the IMD signalling pathway. The expression of the immune gene Relish was significantly reduced by RNAi (ca. 70%). The proposed regulation of antimicrobial peptide genes by Relish could be established for abaecin and hymenoptaecin. These two genes showed a reduction in gene expression to the same extent as Relish. However, the antimicrobial peptide gene defensin-1 was not affected which suggests defensin-1 is regulated by a different signalling pathway.
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RNA interference(RNAi)is a phenomenon of post-transcriptional genes silencing induced by sequence-specific double-stranded RNA(dsRNA).RNAi has become an important tool in the filed of gene therapy.EGFR is over-expressed in cutaneous squamous cell carcinoma,triggering a cascade of downstream signals if activated and resulting in an increase of cellular proliferation,metastasis angiogenesis and blockade of cells apoptosis,which has been developed as a new target for tumor therapy.In this review,we focus on the potential therapeutic use of EGFR targeted RNAi on cutaneous squamous cell carcinoma.
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The insulin-like growth factor-1 receptor (IGF-1R) overexpression contributes to the development of a variety of cancers. The present study explored the role of IGF-1R in the development and progression of hepatocellular carcinoma (HCC) and the possibility of IGF-1R silencing by lentivirus-mediated RNA interference (RNAi) as a therapeutic target for HCC. We showed that IGF-1R mRNA was up-regulated in Huh7 and Hep3B cells and human HCC tissues, and that IGF-1R knockdown by RNAi led to decreased proliferation, apoptosis induction, and decreased migration and invasion of Huh7 and Hep3B cells. Further, the in vivo study indicated that IGF-1R knockdown markedly diminished the tumorigenesis and metastasis of Huh7 xenograft. Moreover, the intratumoral administration of lentivirus-IGF-1R siRNA led to significant tumor growth inhibition in an established Huh7 xenograft model. Mechanistic investigations showed that midkine was found to be the most significantly down-regulated protein in Huh7 cells with IGF-1R knockdown, and ectopic overexpression of midkine significantly rescued inhibition of Huh7 cell proliferation, migration, and invasion caused by IGF-1R suppression. Collectively, these data suggest that IGF-1R inhibition by RNAi can significantly suppress HCC growth and invasion at least partially through down-regulating midkine expression, and IGF-1R is a potential target for HCC gene therapy.
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Small interfering RNA (siRNA) provides a promising therapeutic approach in the silencing of disease‑causing genes. In the present study, the use of 2'‑O‑methyl‑modified siRNA‑cluster of differentiation 31 (siRNACD31), with cationic liposome RNA interference (RNAi)‑mate as a carrier, effectively silenced the platelet endothelial cell molecule 1 (PECAM‑1) gene of murine hemangioendothelioma cells in vitro. In vivo, 2'‑O‑methyl‑modified siRNACD31 carried by RNAi‑mate was successfully delivered, targeting the PECAM‑1 gene in the vasculature of nude mouse lung carcinoma xenografts. The growth of the lung carcinoma xenografts was inhibited by the 2'‑O‑methyl‑modified siRNACD31 and RNAi‑mate complexes, and the expression of the PECAM‑1 protein was downregulated, with a simultaneous decrease in vascular endothelial growth factor (VEGF) protein in the lung carcinoma xenografts. 2'‑O‑methyl‑modified siRNACD31‑RNAi‑mate complexes may provide a potential therapeutic strategy in lung carcinoma treatment. The effect of PECAM‑1 on VEGF expression may possibly be attributed to the function of PECAM‑1 signal transduction.
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Abstract Purpose: The peptidyl-prolyl isomrase Pin1 plays a catalytic role in oncogenesis in solid cancers, including prostate cancer. In the present study, we sought to determine the potential of Pin1-targeted gene silencing in inhibiting cellular growth and tumorigenicity in prostate cancer. Experimental Design: A retrovirus-mediated RNA interference targeting Pin1 was expressed in PC3 and LNCaP cells, and cell growth and several transformed properties were investigated. Results: The stable expression of Pin1-specific small interfering RNA constructs in PC3 and LNCaP cells significantly reduced cellular proliferation, colony formation, migration, and invasion but strongly enhanced the apoptotic response induced by serum depletion or treatment with anticancer agents. Furthermore, Pin1 depletion significantly suppressed tumorigenic potential in athymic mice, resulting in the inhibition of both tumor growth and angiogeneisis. Conclusions: These results strongly suggest that Pin1 plays an important role not only in tumorigenesis but also in the maintenance of the transformed phenotype in prostate cancer cells. Hence, Pin1 may serve as a promising therapeutic target, particularly for recurrent prostate tumors.
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Due to functional redundancy, it is often difficult to genetically analyse the biological function of fungal cell wall-degrading enzymes that belong to a gene family. To overcome this difficulty, we used RNAi to knock-down (KD) multiple xylanase genes to elucidate their roles in the pathogenicity of the blast fungus, Magnaporthe oryzae. To obtain the maximum average efficiency of gene silencing for the xylanase genes, we used the 'building blocks method', in which a 40 bp sequence was chosen from an endoxylanase gene, and 10 such sequences from 10 endoxylanases were combined to make an artificial RNAi trigger by synthetic DNA. Quantitative RT-PCR analysis revealed that the transcript levels of all the expressed xylanase genes were significantly reduced in KD mutants with the artificial RNAi trigger. Even though the KD mutants did not completely lose their pathogenicity to host plants, the number of lesions, rate of penetration and extent of infected cells were all reduced in KD mutant-infected leaves. The degree of pathogenicity reduction was associated with the silencing levels of xylanase mRNA and enzymatic activity in the KD mutants. Cytological analysis indicated that xylanases play significant roles in both vertical penetration and horizontal expansion of M. oryzae in infected plants.
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