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Applications and commercial potential of RNAi.
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[Role of RNA polymerase II in RNAi-dependent heterochromatin formation].
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[RNAi and neurological disease].
In many of autosomal dominant diseases such as familial amyotrophic lateral sclerosis (ALS) with Cu/Zn superoxide dismutase (SOD1) mutation, a missense point mutation may induce the disease by its gain of adverse property. Similar 'gain of toxic function' of mutant protein is predicted to cause cell death in other autosomal dominant neurodegenerative diseases such as familial Alzheimer disease, prion disease, polyglutamine diseases and Parkinson disease. In all these familial diseases, one rational approach to therapy is to develop a method to specifically eliminate the aberrant protein. Duplex of 21-nt RNA, known as siRNA, has recently emerged as a powerful tool to silence gene. Mutant-allele specific gene silencing with siRNA was showed in familial ALS and Machado-Joseph diseases. We made the transgenic (Tg) mouse of modified small interfering RNA (siRNA). By crossing this anti-SOD1 siRNA Tg mouse with a SOD1(G93A) Tg mouse as a model for ALS, siRNA halted the development of disease by inhibiting mutant G93A SOD1. Our results support the feasibility of utilizing siRNA-based gene therapy of neurodegenerative diseases of autosomal dominant inheritance.
EuroTIDES 2005--Sixth Annual IBC Conference. Oligonucleotide, RNAi and peptides for the drug development and manufacturing industry.
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[RNAi gene therapy for kidney disease].
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[RNAi and its application for treatment of cardiovascular diseases].
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[Progress in silencing HBV gene expression by RNAi technologies].
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Effective silencing of EGFR with RNAi demonstrates non-EGFR dependent proliferation of glioma cells.
The epidermal growth factor receptor (EGFR, ErbB1) is frequently dysregulated in a variety of solid human tumors, including malignant glioma. EGFR expression has been associated with disease progression, resistance to standard therapies and poor survival. The application of small interfering RNAs (siRNAs) has become an effective and highly specific tool to modulate gene expression, and a wide range of oncogenes have been silenced successfully. Here we show the siRNA-mediated down-regulation of EGFR in two established glioma cell lines with different EGFR expression levels (U373 MG, LN18). The expression of EGFR mRNA and protein was down-regulated by 70-90%. However, siRNA treatment had no inhibitory effect on cell proliferation, migration and activation status of EGFR-coupled signaling cascades. In accordance with these results, gene expression analysis with microarrays revealed only small, albeit specific changes in expression patterns. In conclusion, these data indicate that the specific down-regulation of EGFR might not be sufficient for a single agent therapeutic approach in malignant glioma.
Mediation of gene silencing by RNAi in non-human primates.
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[Increased sensitivity to chemotherapeutic drug by RNAi targeting Hsp701A in HepG2 cells].
AIM: To investigate the effects on chemotherapeutic sensitivity to the drugs of tumor cells induced by Hsp701A targeting siRNA expression vector. METHODS: Specific small interference RNA (siRNA) targeting Hsp701A gene was generated and its eukaryotic expression vector was constructed and transfected into human HepG2 cells.Sensitivity to the chemotherapeutic drug of HepG2 cells transfected with the vector was detected by MTT colorimetry. RESULTS: The eukaryotic expression vector of siRNA targeting Hsp701A was successfully constructed and transfected into human HepG2 cells. Sensitivity to the chemotherapeutic drug of HepG2 cells was increased after Hsp701A was knock down (P<0.05). CONCLUSION: Knockdown of Hsp701A gene by siRNA enhances sensitivity to chemotherapeutic drug in HepG2 cells.
[Study on apoptosis of oral squamous carcinoma cell line KB and KBv200 induced by survivin RNAi].
BACKGROUND & OBJECTIVE: Survivin, a member of IAPs (inhibition of apoptosis proteins) family, has been revealed by many studies to inhibit the activation of caspase-3, caspase-7 and caspase-9, and thus increase the anti-apoptotic effect of cancer cells, which subsequently makes the cells to become resistant to chemotherapy in cancer treatment. Survivin is expressed in human oral squamous carcinoma cell line KB and its multiple-drug resistant (MDR) cell line KBv200. This study was to compare the apoptosis induced by silencing survivin gene between these two squamous cell lines. METHODS: Mu6/survivin plasmid which expressed shRNA against survivin was transfected into both KB and KBv200 cells to inhibit the expression of survivin gene. Survivin mRNA and protein expression was detected by semi-quantitative RT-PCR and flow cytometry (FCM), respectively. Cell apoptotic rate was measured by flow cytometry after PI staining, and apoptotic morphology of cells was observed under a fluorescent microscope after Hoechst33258 staining. Activation of caspase-3 was measured by colorimetric assay. MTT was used to evaluate the growth inhibition of tumor cells. RESULTS: Expression of survivin, which was higher in KBv200 at mRNA and protein level, was detected in both KB and KBv200. After 48 h transfection with mu6/survivin plasmid, the expression level of survivin mRNA in KB and KBv200 was reduced by (61.98+/-8.12)% and (59.29+/-6.32)%; and that of survivin protein was decreased by (44.25+/-5.26)% and (38.76+/-4.31)% compared with the control group. Moreover, KB and KBv200 cells exhibited typical apoptotic cell morphology by Hoechst 33258 staining. Apoptosis, which was higher in KB cells, was increased significantly at 24, 48, 72 h after the transfection of mu6/surviving in KB and KBv200 cells, and reached the peak at 48 h. Similarly, activation of caspase-3 was elevated significantly, and reached the peak at 48 h. MTT assay revealed the inhibitory rates were (33.04+/-2.16)%, (56.25+/-3.32)% and (58.26+/-5.14)% in KB cells, and (35.23+/-3.42)%, (44.90+/-4.12)% and (44.19+/-4.37)% in KBv200 cells at 24, 48, 72 h after the transfection, respectively. Growth rate was lower in KB cells at 48, 72 h after the transfection compared with KBv200 cells. CONCLUSION: RNA interference could silence the expression of survivin, which significantly induces apoptosis not only in KB cells, but also in drug resistant KBv200 cells.
[Inhibition of HBV replication and expression by RNAi].
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[Inhibition of survivin gene expression in PC-3 cells by RNAi].
OBJECTIVE: To construct eukaryotic expression vectors by using the pSilencer3. 1-H1 neo vector for inhibiting human survivin gene by RNA interference, and to detect the effect of the silenced survivin gene on PC-3 cells. METHODS: Three target gene segments were synthesized and cloned into the pSilencer3. 1-H1 neo vector respectively to construct three recombinant eukaryotic expression vectors: pSilencer3. 1-SVV1, pSilencer3. 1-SVV2 and pSilencer3. 1-SVV3, which were identified by enzyme digestion analysis and DNA sequencing. Then the PC-3 cells were transfected with the recombinant vectors and the interference effect detected by RT-PCR, Western blot and immunohistochemical staining. The apoptosis index of the PC-3 cells was detected by flow cytometry and their proliferation detected by MTT method. RESULTS: Enzyme digestion analysis and DNA sequencing showed that three target segments were cloned into pSilencer3. 1-H1-neo vectors. The results of RT-PCR, Western blot and immunohistochemical staining indicated that pSilencer3. 1-SVV2 and pSilencer3. 1-SVV3 vectors could knock down the transcription and expression of survivin gene. After transfected with pSilencer3. 1-SVV2 and pSilencer3. 1-SVV3 vectors, the apoptosis index of the PC-3 cells was increased by 10% - 15% and their growth obviously slowly down. CONCLUSION: The transcription and expression of survivin gene were inhibited effectively by the recombinant eukaryotic expression vectors (pSilencer3. 1-SVV2 and pSilencer3. 1-SVV3) in the prostate cancer cell line PC-3. After transfected with pSilencer3. 1-SVV2 and pSilencer3. 1-SVV3 vectors, the apoptosis index of the PC-3 cells was increased and their growth inhibited.
Plants, RNAi, and the Nobel Prize.
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[RNAi, Fire (see text) Mello].
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Loss of LIN-35, the Caenorhabditis elegans ortholog of the tumor suppressor p105Rb, results in enhanced RNA interference.
BACKGROUND: Genome-wide RNA interference (RNAi) screening is a very powerful tool for analyzing gene function in vivo in Caenorhabditis elegans. The effectiveness of RNAi varies from gene to gene, however, and neuronally expressed genes are largely refractive to RNAi in wild-type worms. RESULTS: We found that C. elegans strains carrying mutations in lin-35, the worm ortholog of the tumor suppressor gene p105Rb, or a subset of the genetically related synMuv B family of chromatin-modifying genes, show increased strength and penetrance for many germline, embryonic, and post-embryonic RNAi phenotypes, including neuronal RNAi phenotypes. Mutations in these same genes also enhance somatic transgene silencing via an RNAi-dependent mechanism. Two genes, mes-4 and zfp-1, are required both for the vulval lineage defects resulting from mutations in synMuv B genes and for RNAi, suggesting a common mechanism for the function of synMuv B genes in vulval development and in regulating RNAi. Enhanced RNAi in the germline of lin-35 worms suggests that misexpression of germline genes in somatic cells cannot alone account for the enhanced RNAi observed in this strain. CONCLUSION: A worm strain with a null mutation in lin-35 is more sensitive to RNAi than any other previously described single mutant strain, and so will prove very useful for future genome-wide RNAi screens, particularly for identifying genes with neuronal functions. As lin-35 is the worm ortholog of the mammalian tumor suppressor gene p105Rb, misregulation of RNAi may be important during human oncogenesis.