Regression of A549 lung cancer tumors by anti-miR-150 vector

Abstract

Abstract. microRNAs (miRNAs) have been shown to play a role in cancer. Antisense oligonucleotides can bind directly to miRNAs and block their activity, which are generally named anti-miRNAs. To suppress A549 cell proliferation in vitro and in vivo by anti-miRNAs, an anti-miR-150 expression vector (PR-ASO-150), regulated by the H1 promoter and containing a 'TTTTT' sequence following a hairpin to stop transcription, was constructed. A549 cell proliferation in vitro or in nude mice was observed after PR-ASO-150 treatment. Our results showed that miR-150 expression was inhibited and the growth inhibition rate of A549 cells was higher in the PR-ASO-150-treated group compared with the control, which indicated that PR-ASO-150 could inhibit A549 cell proliferation by regulating miR-150 expression. Following establishment of A549 cancer cell xenografts in nude mice, PR-ASO-150 was delivered intratumorally to investigate the suppressive action to tumor proliferation by regulating miR-150 expression. The results indicate that the tumor volume and weight were lower compared to the control group. Our results further showed that p53 expression was higher after tumor tissue was treated with PR-ASO-150, indicating that up-regulation of p53 contributed to the suppression to tumor growth. Our study provides a novel strategy for cancer therapy through the development of antimiRNAs.Introduction microRNAs (miRNAs) are small non-coding RNA molecules (19-22 nucleotides) that bind to mRNA in a sequence-specific manner (1). Through complementary binding to mRNA targets, each microRNA has the distinct capability to potentially regulate the expression of hundreds of genes and thereby modulates several cellular pathways including proliferation and apoptosis (2).Importantly, miRNAs play critical roles in the development and progression of several types of cancers (3,4). Dependent upon the nature of their target gene(s), miRNAs may function as tumor suppressors by down-regulating target oncogenes (e.g. let-7 and miR-15/16) or as oncogenes by negatively controlling genes that regulate tumor cell differentiation and apoptosis (e.g. miR-155 and miR-21) (5). Indeed, several miRNAs are reported to have important roles in different types of cancer, including acute myelogenous leukemia (6,7), chronic myelogenous leukemia (CML) (8-10), lung cancer (11,12), and breast cancer (13), among others. miRNAs have also been shown to play a role in cancer progression through the modulation of cellular adhesion, cell matrix and signaling activities (14,15). In addition, miRNAs have been shown to regulate the expression of hypoxia-related genes and of the vascular endothelial growth factor (16,17).Emerging evidence shows that deregulation of miRNAs may be a primary driver of cancer initiation and progression. The rules of Watson and Crick base-pairing guide the binding of miRNAs to their target genes. In order to circumvent this interaction, anti-microRNA oligonucleotides (AMOs) have been generated to directly compete with endogenous miRNAs (18). Several modifi...

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