Development of RNA Interference–Based Therapeutics and Application of Multi-Target Small Interfering RNAs

Li, Tiejun; Wu, Ming-Shiou; Zhu, York Yuanyuan; Chen, Jianxin; Chen, Li

doi:10.1089/nat.2014.0480

Cited by 23 publications

(13 citation statements)

References 107 publications

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“…The RNAi machinery recognizes its RNA targets through dsRNA in a sequence-specific manner, and can efficiently knock down endogenous or exogenously introduced dsRNAs 6 . The RNAi technique has been well developed and widely used to study gene function, and has become a popular and reliable tool to greatly enhance understanding of molecular and genetic mechanisms of human diseases, leading to promising therapeutic application 7 8 9 . By using genome-wide RNAi libraries, almost any gene can be selectively silenced, and the process can be accomplished in a high throughput and unbiased manner.…”

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confidence: 99%

A large-scale in vivo RNAi screen to identify genes involved in Notch-mediated follicle cell differentiation and cell cycle switches

Jia

Soylemez

Calvin

et al. 2015

Sci Rep

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During Drosophila oogenesis, follicle cells sequentially undergo three distinct cell-cycle programs: the mitotic cycle, endocycle, and gene amplification. Notch signaling plays a central role in regulating follicle-cell differentiation and cell-cycle switches; its activation is essential for the mitotic cycle/endocycle (M/E) switch. Cut, a linker between Notch signaling and cell-cycle regulators, is specifically downregulated by Notch during the endocycle stage. To determine how signaling pathways coordinate during the M/E switch and to identify novel genes involved in follicle cell differentiation, we performed an in vivo RNAi screen through induced knockdown of gene expression and examination of Cut expression in follicle cells. We screened 2205 RNAi lines and found 33 genes regulating Cut expression during the M/E switch. These genes were confirmed with the staining of two other Notch signaling downstream factors, Hindsight and Broad, and validated with multiple independent RNAi lines. We applied gene ontology software to find enriched biological meaning and compared our results with other publications to find conserved genes across tissues. Specifically, we found earlier endocycle entry in anterior follicle cells than those in the posterior, identified that the insulin-PI3K pathway participates in the precise M/E switch, and suggested Nejire as a cofactor of Notch signaling during oogenesis.

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confidence: 99%

A large-scale in vivo RNAi screen to identify genes involved in Notch-mediated follicle cell differentiation and cell cycle switches

Jia

Soylemez

Calvin

et al. 2015

Sci Rep

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“…It is known that RNAi-based therapy is effective and elicit gene silencing response, the double-stranded RNA molecules must be delivered to the target cells. Unfortunately, the specific delivery of RNAi has been challenging despite many efforts made in the last few years and the intratumoral injection of RNAi has emerged as a promising alternative to overcome this obstacle (19,20). We also decided to investigate the effect of the intratumoral injection of CXCR4 shRNA expressing plasmid in the pre-established subcutaneous B16-F10 melanoma.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of chemokine receptor CXCR4 gene by RNA interference: Effects on the B16-F10 melanoma growth

et al. 2016

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The incidence of malignant melanoma has increased greatly in recent decades presenting a high mortality rate despite intensive efforts in this area of research. Recent studies indicate that the chemokine receptor 4 (CXCR4) plays a critical role in cancer. Thus, it has been reported that CXCL12 binding to CXCR4 initiates various downstream signaling pathways that result in a plethora of responses involved in cell proliferation and metastasis. Recently, we demonstrated that CXCR4 silencing by RNA interference (RNAi) significantly reduced the number of pulmonary metastatic nodules. In the present study, we examined the effect of the intratumoral injection of CXCR4 short hairpin (shRNA) expressing plasmids on the growth of B16‑F10 melanoma in mice. In vitro transfection of these tumor cells with CXCR4 shRNA expressing plasmid (CXCR4 shRNA) significantly reduced the levels of CXCR4 mRNA (85%) and CXCR4 protein (70%) compared with the control. We showed that the tumor growth was significantly reduced (66%) in mice inoculated with transfected B16‑F10 melanoma cells when compared with the control group. We also found that the intratumoral injection of CXCR4 shRNA expressing plasmids results in a significant inhibition (70%) of B16‑F10 melanoma growth. This finding supports the hypothesis that a direct administration of RNAi‑based therapeutics into the target tumor is a promising approach for overcoming the hurdles of systemic delivery. The present study is the first demonstration that CXCR4 plays a critical role in B16-F10 melanoma growth. Currently there is great interest in the development of antagonists for therapeutic targeting CXCR4 expression. Considering our results and the fact that CXCR4 is highly conserved between human and mouse, this experimental model of cancer may be useful for the discovery of new CXCR4 antagonists with clinical implications.

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“…Now, it has been confirmed that RNAi has great potential in treatment of various human diseases, such as viral infections (5,6), cancers (7-10) and orphan disease (11). Recently, an attempt using a long double-strand siRNA was made, as an alternative way, to carry on multiple interfering RNAs (iRNA) for multiple gene suppression for treatment of many human diseases (12)(13)(14), such as therapy for hepatocellular carcinoma (HCC) (10). Currently there are more than thirty types of siRNA drug candidates entered into the stage of clinical trials (15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Interfering RNA with multi-targets for efficient gene suppression in HCC cells

Zhu

et al. 2018

Int J Mol Med

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RNA interference (RNAi) technology has been widely used in therapeutics development, especially multiple targeted RNAi strategy, which is a better method for multiple gene suppression. In the study, interfering RNAs (iRNAs) were designed for carrying two or three different siRNA sequences in different secondary structure formats (loop or cloverleaf). By using these types of iRNAs, co-inhibition of survivin and B-cell lymphoma-2 (Bcl-2) was investigated in hepatocellular carcinoma (HCC) cells, and we obtained promising gene silencing effects without showing undesirable interferon response. Furthermore, suppression effects on proliferation, invasion, and induced apoptosis in HCC cells were validated. The results suggest that long iRNAs with secondary structure may be a preferred strategy for multigenic disease therapy, especially for cancer and viral gene therapy and their iRNA drug development.

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Development of RNA Interference–Based Therapeutics and Application of Multi-Target Small Interfering RNAs

Cited by 23 publications

References 107 publications

A large-scale in vivo RNAi screen to identify genes involved in Notch-mediated follicle cell differentiation and cell cycle switches

A large-scale in vivo RNAi screen to identify genes involved in Notch-mediated follicle cell differentiation and cell cycle switches

Knockdown of chemokine receptor CXCR4 gene by RNA interference: Effects on the B16-F10 melanoma growth

Interfering RNA with multi-targets for efficient gene suppression in HCC cells

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