The Disappeared Cancer Cell by SncRNAs: Application of DDMC Vector/SncRNAs Complex for Transformation of Cancer Cells into Non-cancerous Cells
Received Date: Jan 22, 2018 / Accepted Date: Jan 25, 2018 / Published Date: Jan 30, 2018
DDMC/sncRNAs (Diethylaminoethyl-Dextran-Methacrylic acid Methyl ester Copolymer/small non-coding RNAs) complex is a new tool for the anticancer treatment. It consists of DDMC polymer delivery system with sncRNAs as passengers. The main function of DDMC carrier is supporting of the entrance of sncRNAs in the nucleus/cytoplasm and protection them from rapid biodestruction by DNases and RNases in plasma and cellular matrix. After getting inside the nucleus, sncRNAs epigenetically induce and promote cancer cells genome modifications, and finally result in cancer cell transformation. In primary investigations were used complexes by DDMC/miRNAs (microribonucleic acid and piRNAs (piwi-interacting ribonucleic acid). Its slow velocity of biodegradation helps to prolong epigenetic regulation of cellular genome by sncRNAs, near 40 days in in vitro experiments.
DDMC carrier is very stable in vivo and has EPR (Enhanced permeation and retention) effect and avoiding RES (reticuloendothelial system). Mechanisms of protection activity of DDMC carrier for sncRNAs and supporting of low velocity of biodegradation are mainly owe to its stable properties. This may be due not only to the coulomb force between the phosphoric acid of RNA and the diethyl-aminoethyl( DEAE) group of DDMC but also a force from the multi-intermolecule hydrogen bond and a hydrophobic force from the hydrophobic domains of the graft poly(MMA) in DDMC. These lead us to conclude that DNA/RNA condensation by a coil-globule transition for DDMC, thus make it possible to obtain higher transfection efficiency in the cell and nucleus. The new type of polymer carrier have good RNA protection properties, high transfection efficiency index (11-30 days) and it’s rate is 70-98% in different cell types, low toxicity of DDMC/sncRNAs complex after treatment in vitro and in vivo experiments . After entrance into the cytosol, DDMC/sncRNAs complexes are partially biodegrade and small part of sncRNAs such as miRNAs can react with mRNA in cellular matrix. In cytosol, it is beginning primary effects after action of miRNAs, which were incorporated in complex DDMC/sncRNAs. These events result in modification of mRNA on the post-transcriptional level (Figure 1). MiRNAs trigger gene comes to silencing by the mean of RNA interference mechanisms. The functions of oncogenic miRNAs are suppressed after using of particular antago-miRs for oncogenic miRNAs, and vice versa, the action of anti-oncogenic miRNAs is promoted after treatment with anti-oncogenic miRNAs. In previous studies, were identified different miRNAs or antago-miRs, which regulated apoptotic program of cancer cells. For example, miR-15 and miR-16 expression modify the expression of Bcl2, miR-26 induced apoptosis in liver cancer cells, and miR-29b promote apoptotic program in AML cells. Treatment with antago-miR for miR-15, miR-16, and let- 7 result in activation of apoptosis in cancer cells, treatment of cells with miR-195, miR-24-2 and miR-365 led to induction of apoptosis in breast cancer cells. MiR-34 is apoptosis inducer in liver cancer cells. AntagomiR- 155 induces caspase 8/9 activity and miR-152 activates apoptosis and inhibits proliferation in lung cancer cells [2-11].
Full reprogramming of cancer cell genome achieved after entrance of DDMC/sncRNAs complex in the nucleus and complex biodegradation. In the nucleus, it begins action of miRNAs and piRNAs, which are slowly disengaging from the binding with DDMC. PiRNAs trigger deep re-construction of genetic program of cell. The main function of piRNAs is supporting of cellular genome stability. The main mechanisms of piRNAs action are mobile genomic transposable elements (TE) repression (LINE and SINE are natural pathogenic factors in cancers) . PiRNAs suppress of NAHR non-allelic homologous recombination and they protect genome stability by expression H3K9me, and histone modification (suppression of position effect variegation) [13-15].
Besides, in the complex is included miRNAs, which trigger differentiation of cells. In previous investigations were confirmed the role of different miRNAs in cellular differentiation [16-23]. After releasing from the DDMC/sncRNAs complex, these miRNAs in cooperation with piRNAs switch-on complex mechanisms of full cellular transformation. Finally, cancer cells transform into physiologically non-cancerous cells.
DDMC/SncRNAs helps to prolong epigenetic regulation of cellular genome by sncRNAs, near 40 days in in vitro experiments owing to disturb its biodegradation. In this periods, DDMC/SncRNAs as one body epigenetically will induce and promote cancer cells genome modifications. At this time, Gene control by DDMC/SncRNAs is shown by Hill Eq. and will take “Robustness feedback Control Systems” sustainably as bellows;
General form of Hill Eq. is
Here, Kn < Xn, β is active Allosteric factor. If X is inlet signal and Y is outlet signal in tumor microenvironment.
Then, F(X) = β , F(X) =αY , and ΔF(X) = dY/dt at α>0, β>0 in allosteric regulation in this tumor micro environment.
The differential variation of ΔF(X) = β−αY , then
Outlet signal Y in Eq.(1) limits to β/α as α>0.
- Klimenko OV (2017) Toxicity and transfection efficiency of new non-viral delivery systems for small non-coding RNAs: Amphiphilic poly(N-vinylpyrrolidone) and Diethylaminoethyl-Dextran-Methacrylic acid Methyl ester Copolymer. Adv Sci Eng Med 9: 426-431.
- Huang X, Schwind S, Yu B, Santhanam R, Wang H, et al. (2013) Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles: a novel therapeutic strategy in acute myeloid leukemia. Clin Cancer Res 19: 2355-23567.
- Singh R, Saini N (2012) Downregulation of BCL2 by miRNAs augments drug-induced apoptosis-a combined computational and experimental approach. J Cell Sci 125: 1568-1578.
- Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, et al. (2005) MiR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 102: 13944-13949.
- Bouchie A (2013) First microRNA mimic enters clinic. Nat Biotechnol 31: 577.
- Daige CL, Wiggins JF, Priddy L, Neligan-Davis T, Zhao J, et al. (2014) Systemic delivery of a miR34a mimic as a potential therapeutic for liver cancer. Mol Cancer Ther 13: 2352-2360.
- Agostini M, Knight RA (2014) MiR-34: from bench to bedside. Oncotarget 5: 872-881.
- Pileczki V, Cojocneanu-Petric R, Maralani M, Neagoe IB, Sandulescu R (2016) MicroRNAs as regulators of apoptosis mechanisms in cancer. Clujul Medical 89: 50-55.
- Klimenko OV (2017) Joint action of the nano-sized system of small non-coding RNAs with DDMC vector and recombinant IL-7 reprograms A-549 lung adenocarcinoma cells into CD4+ cells. Immunother (Los Angel) 3: 137.
- Liu X, Li J, Qin F, Dai S (2016) MiR-152 as a tumor suppressor microRNA: target recognition and regulation in cancer. Oncol Lett 11: 3911-3916.
- Zhang YJ, Liu XC, Du J, Zhang YJ (2015) MiR-152 regulates metastases of non-small cell lung cancer cells by targeting neuropilin-1. Int J Clin Exp Pathol 8: 14235-14240.
- Klimenko OV (2017) Small non-coding RNAs as regulators of structural evolution and carcinogenesis. Non-coding RNA Res 2: 88-92.
- Pal-Bhadra M, Leibovitch BA, Gandhi SG, Rao M, Bhadra U, et al. (2004) Heterochromatic silencing and HP1 localization in Drosophila are dependent on the RNAi machinery. Science 303: 669-672.
- Brower-Toland B, Findley SD, Jiang L, Liu L, Yin H, et al. (2007) Drosophila PIWI associates with chromatin and interacts directly with HP1a. Genes Dev 21: 2300-2310.
- Yin H, Lin H (2007) An epigenetic activation role of Piwi and a Piwi-associated piRNA in Drosophila melanogaster. Nature 450: 304-308.
- Tian Y, Guo R, Shi B, Chen L, Yang L, et al. (2016) MicroRNA-30a promotes chondrogenic differentiation of mesenchymal stem cells through inhibiting Delta-like 4 expression. Life Sci 148: 220-228.
- Otto T, Candido SV, Pilarz MS, Sicinska E, Bronson RT, et al. (2017) Cell cycle-targeting microRNAs promote differentiation by enforcing cell-cycle exit. Proc Natl Acad Sci USA 114: 10660-10665.
- Jin M, Wu Y, Wang Y, Yu D, Yang M, et al. (2016) MicroRNA-29a promotes smooth muscle cell differentiation by targeting YY1. Stem Cell Res 17: 277-284.
- Chen CH, Lu HT, Tsuang YH, Kuo YJ (2017) MicroRNA-215 promotes proliferation and differentiation of osteoblasts by regulation of c-fos. Int J Clin Exp Pathol 10: 6536-6543.
- Le MTN, Xie H, Zhou B, Chia PH, Rizk P, et al. (2009) MicroRNA-125b promotes neuronal differentiation in human cells by repressing multiple targets. Mol Cell Biol 29: 5290-5305.
- Fujii T, Shimada K, Tatsumi Y, Hatakeyama K, Obayashi C, et al. (2015) MicroRNA-145 promotes differentiation in human urothelial carcinoma through down-regulation of syndecan-1. BMC Cancer 15: 818.
- Ma H, Lin Y, Zhao Z-A, Lu X, Yu Y, et al. (2016) MicroRNA-127 promotes mesendoderm differentiation of mouse embryonic stem cells by targeting left-right determination factor 2. J Biol Chem 291: 12126-12135.
- Klimenko OV, Shtilman MI (2013) Transfection of Kasumi-1 cells with a new type of polymer carriers loaded with miR-155 and antago-miR-155. Cancer Gene Ther 20: 237-241.
Citation: Klimenko OV, Onishi Y (2018) The Disappeared Cancer Cell by SncRNAs: Application of DDMC Vector/SncRNAs Complex for Transformation of Cancer Cells into Non-cancerous Cells. J Nanomedine Biotherapeutic Discov 8: e147. Doi: 10.4172/2155-983X.1000e147
Copyright: © 2018 Klimenko OV, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Select your language of interest to view the total content in your interested language
Share This Article
- Total views: 64
- [From(publication date): 0-2018 - Jul 18, 2018]
- Breakdown by view type
- HTML page views: 46
- PDF downloads: 18