Abstract
MicroRNAs play an important role in tumorigenesis and, among them, miR-21 is found to be aberrantly up-regulated in various tumors. The tumor-associated antigen, folate receptor alpha is a GPI-membrane protein overexpressed in many malignant tumors of epithelial origin, including ovarian and cervical cancers. Covalently bound octahedral DNA nanocages were functionalized with folate molecules and utilized as scaffolds to engineer four sequestering units with a miR-21 complementary sequence for obtaining biocompatible Fol-miR21-NC non-toxic nanostructures, to be able to selectively recognize folate receptor alpha-overexpressing cancer cells and sequester the oncogenic miR-21. qPCR assays showed that Fol-miR21-NCs reduce the miR-21 expression up to 80% in cancer cells in the first 2 days of treatment. Functional assays demonstrated that miR-21 sequestering leads to up-regulation of miR-21 tumor suppressor targets (i.e., PTEN and Pdcd4), reduction in cancer cell migration, reduction in proliferation, and increase in cell death. Fol-miR21-NCs can be efficiently loaded with the chemotherapeutic agent doxorubicin. Co-delivery of anti-miR-21 and doxorubicin showed additive cytotoxic effects on tumor cells, paving the way for their use as selective nucleic acid drugs.
Highlights
Introduction Aberrant expression ofmicroRNAs has been reported in various tumors indicating that there is a close correlation between miRNAs and human malignancy
Therapeutic effects of Fol-miR21-NCs on cancer cells To demonstrate the biological effects of miR-21 knockdown, we studied the expression level of PTEN and Pdcd[4], two known downstream targets regulated by miR-21
Here we demonstrate that functionalized DNA nanocages (Fol-NCs) engineered with four sequestering units complementary to miR-21, for inhibiting miR-21 function, enter the cells through the α-isoform of the folate receptor (αFR)-mediated route and sequester miR-21 within cells, leading to 70–80% reduction in either IGROV1 or HeLa cells, after 48 h treatment
Summary
Introduction Aberrant expression ofmicroRNAs (miRNAs) has been reported in various tumors indicating that there is a close correlation between miRNAs and human malignancy. MiRNAs are involved in many biological processes, such as cell proliferation and apoptosis, by regulating gene expression at post-transcriptional level[1]. Dysregulation in the expression of different miRNAs contributes to cancer development and progression[2,3,4,5,6,7]. Dysregulation of miR-21 expression is related with the proliferation, apoptosis, and migration of cancer cells[9]. The increase in miR-21 levels in cancer cells was found to down-regulate tumor suppressor proteins, PTEN and programmed cell death protein 4 (Pdcd4), and to regulate different apoptotic genes[10]. These observations suggest miR-21 knockdown as a promising anticancer therapeutic strategy. To minimize off target side effects and avoid unexpected collateral damage in normal cells, a targeted therapy becomes crucial[12]
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