Targeting oncomiRNAs and mimicking tumor suppressor miRNAs: Νew trends in the development of miRNA therapeutic strategies in oncology (Review)

Abstract

MicroRNA (miRNA or miR) therapeutics in cancer are based on targeting or mimicking miRNAs involved in cancer onset, progression, angiogenesis, epithelial-mesenchymal transition and metastasis. Several studies conclusively have demonstrated that miRNAs are deeply involved in tumor onset and progression, either behaving as tumor-promoting miRNAs (oncomiRNAs and metastamiRNAs) or as tumor suppressor miRNAs. This review focuses on the most promising examples potentially leading to the development of anticancer, miRNA-based therapeutic protocols. The inhibition of miRNA activity can be readily achieved by the use of miRNA inhibitors and oligomers, including RNA, DNA and DNA analogues (miRNA antisense therapy), small molecule inhibitors, miRNA sponges or through miRNA masking. On the contrary, the enhancement of miRNA function (miRNA replacement therapy) can be achieved by the use of modified miRNA mimetics, such as plasmid or lentiviral vectors carrying miRNA sequences. Combination strategies have been recently developed based on the observation that i) the combined administration of different antagomiR molecules induces greater antitumor effects and ii) some anti-miR molecules can sensitize drug-resistant tumor cell lines to therapeutic drugs. In this review, we discuss two additional issues: i) the combination of miRNA replacement therapy with drug administration and ii) the combination of antagomiR and miRNA replacement therapy. One of the solid results emerging from different independent studies is that miRNA replacement therapy can enhance the antitumor effects of the antitumor drugs. The second important conclusion of the reviewed studies is that the combination of anti-miRNA and miRNA replacement strategies may lead to excellent results, in terms of antitumor effects.

Figure 1

(A) Scheme outlining the ability of miRNAs to promote cancer and metastasis (green arrowed line) or to suppress mRNAs coding oncoproteins (red line). (B) Examples of proposed approaches for the development of therapeutic protocols to modulate the biological activity of miRNAs involved in cancer. The objectives of these molecular interventions are the downregulation of oncomiRNAs and metastamiRNAs (orange arrow) or the upregulation/mimicking of onco-suppressor miRNAs (green arrow). Modified from Ghelani et al (3).

Figure 2

(A) miRNA replacement therapy: partial list of tumor suppressor miRNAs (in the blue box) and selected examples of the in vivo restoration of miR-29b (97) and of miR-30b (142), leading to the inhibition of tumor cell growth. (B) Targeting oncomiRNAs and metastamiRNAs with antagomiRNAs: partial list of onco/metastamiRNAs and a selected example of the antitumor effects of antagomiR-17-5p (255).

Figure 3

Epithelial-mesenchymal transition (EMT), a powerful process leading to tumor invasion and metastasis. Examples of EMT-promoting miRNAs are reported in the green box, while examples of EMT-interfering miRNAs are reported in the pink box. Modified from Kiesslich et al (323).

Figure 4

(A) Transfection of U251 glioma cells with pre-miR-93 leads to the downregulation of interleukin-8 (IL-8) (upper panel) and vascular endothelial growth factor (VEGF; lower panel) protein expression. (B) Scheme outlining the effects of pre-miR-93 on neoangiogenesis and tumor growth in gliomas. Modified from Fabbri et al (344).

Figure 5

(A–D) Co-administration of R8-conjugated PNAs against miR-221 (R8-PNA-a221) and miR-222 (R8-PNA-a222) exhibits increased effects on the apoptosis of treated U251 glioma cells. Human glioma U251 cells were cultured (A) without, or (B) in the presence of 4 μM R8-PNA-a221, (C) 4 μM R8-PNA-a222 or (D) 2 μM R8-PNA-a221 plus 2 μM R8-PNA-a222. After 48 h of treatment, an analysis of the induction of apoptosis was conducted using the Annexin V assay and the Muse instrument, as described in detail in the study by Brognara et al (56). (E) Quantitative results derived by the data shown in (A–D). The most potent apoptosis-inducing effects were observed with the co-treatment of the U251 cells with R8-PNA-a221 and R8-PNA-a222. Modified from Brognara et al (358).

Figure 6

Treatment of U251 glioma cells with (B) 10 nM pre-miR-124, (C) 4 μM R8-PNA-a221 targeting miR-221 or (D) a combined administration of 10 nM pre-miR-124 and 4 μM R8-PNA-a221. (A) Control untreated cells are shown. After 48 h of treatment, the effects on apoptosis were analyzed by the caspase-3/7 assay and the Muse instrument. (E) Quantitative results derived by the data shown in (A–D). The most potent apoptosis-inducing effects were observed with the co-treatment of U251 cells with R8-PNA-a221 and pre-miR-124 (Fabbri et al, unpublished data).