Abstract
Dysregulation of miRNA expression has been implicated in cancer. Numerous strategies have been explored to modulate miR but sub-optimal delivery and inability to concurrently target multiple pathways involved in tumor progression have limited their efficacy. In this study, we explored the potential co-modulation of upregulated miR-21 and downregulated miR-7 to enhance therapeutic outcomes in heterogenic tumor types. We first engineered lentiviral (LV) and adeno-associated viral (AAV) vectors that preferentially express anti-sense miR against miR-21(miRzip-21) and show that modulating miR-21 via miRzip extensively targets tumor cell proliferation, migration and invasion in vitro in a broad spectrum of cancer types and has therapeutic efficacy in vivo. Next, we show a significantly increased expression of caspase-mediated apoptosis by simultaneously downregulating miR-21 and upregulating miR-7 in different tumor cells. In vivo co-treatment with AAV-miRzip-21 and AAV-miR-7 in mice bearing malignant brain tumors resulted in significantly decreased tumor burden with a corresponding increase in survival. To our knowledge, this is the first study that demonstrates the therapeutic efficacy of simultaneously upregulating miR-7 and downregulating miR-21 and establishes a roadmap towards clinical translation of modulating miRs for various cancer types.
Highlights
MicroRNAs are a class of small noncoding RNA that are involved in biological processes such as proliferation, differentiation, apoptosis and development[1,2]
Down regulation of miR-21 induces apoptosis through targeting PI3K/AKT and JAK/STAT3 signaling pathways[7] and has a potential to collaborate or synergistically act with other miRs and fine-tune protein output17. microRNA-7 is an intronic microRNA that resides in the first intron of the heterogeneous ribonuclear protein K gene on chromosome 918 and is down regulated in different cancer types[19,20,21,22,23,24,25]
room temperature (RT)-PCR analysis on LV-miRzip-21 transduced cells showed that miR-21 expression levels were significantly reduced as compared to control groups (Fig. 1E,F) resulting in a significant reduction in cell viability (Fig. 1G) in all cancer types including the primary patient derived GBM stem cells (GSCs)
Summary
MicroRNAs (miRs) are a class of small noncoding RNA that are involved in biological processes such as proliferation, differentiation, apoptosis and development[1,2]. We have shown that forced expression of miR-7 in GBM cells results in down-regulation of EGFR and p-AKT, leading to activation of the NFkB signaling[26] As both miR-21 and miR-7 activate different yet synergistic pathways and could be a contributing factor in tumor heterogeneity, it is essential to explore the potential of co-modulation of miR-7 and miR-21 that can target complementary pathways affecting tumor growth and development. Two different strategies for miR-targeting therapy have been explored namely, activation or upregulation of tumor suppressor miRs and inhibiting the function of oncomiRs4. Traditional methods have presented numerous caveats such as their transient nature of inhibition and several stoichiometric restrictions that have limited the success of the anti-miR approach Novel expression systems such as miRzip have been developed to alleviate these issues. We first assessed the role of modulating oncogenic miR-21 via miRzip in a broad spectrum of cancer types and explored the therapeutic effects elicited by simultaneous targeting miR-21 and tumor suppressor, miR-7 in various cancer types in vivo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
