Small non-coding RNAs control normal development and differentiation in the embryo. These regulatory molecules play a key role in the development of human diseases and are used often today for researching new treatments for different pathologies. In this study, CaCo2 colorectal adenocarcinoma cells were initially epigenetically reprogrammed and transformed into CD4+ cells with nano-sized complexes of amphiphilic poly-(N-vinylpyrrolidone) (PVP) with miRNA-152 and piRNA-30074. The transformation of cells was confirmed by morphological and genetic changes in the dynamic of reprogramming. CD4+ lymphocytes marker was detected using immunofluorescence. Amphiphilic poly-(N-vinylpyrrolidone)/small non-coding RNAs complexes were investigated for transfection efficiency and duration of transfection of CaCo2 colorectal adenocarcinoma cells using fluorescence.

Department of Biomaterials D 1 Mendeleyev University of Chemical Technology 9 Miusskaya Square Moscow 125047 Russia

SID ALEX GROUP LTD Kyselova 1185 2 Prague 182 00 Czechia

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Siomi M.C., Sato K., Pezic D., Aravin A.A. PIWI-interacting small RNAs: the vanguard of genome defence. Nat. Rev. 2011;12:246–258. PubMed

Klimenko O.V., Onishi Y. The disappeared cancer cell by sncRNAs: application of DDMC vector/sncRNAs complex for transformation of cancer cells into non-cancerous cells. J. Nanomed. Biother. Discov. 2018;8:1–2.

Klimenko O.V. Small non-coding RNAs as regulators of structural evolution and carcinogenesis. Noncoding RNA Res. 2017;2:88–92. PubMed PMC

Pulito C., Donzelli S., Muti P., Puzzo L., Strano S., Blandino G. microRNAs and cancer metabolism reprogramming: the paradigm of metformin. Ann. Transl. Med. 2014;2:58. PubMed PMC

Hatziapostolou M., Polytarchou C., Iliopoulos D. miRNAs link metabolic reprogramming to oncogenesis, Trends Endocrinol. Metabolism. 2013;24:361–373. PubMed

Lewis B.P., Shih I.H., Jones-Rhoades M.W., Bartel D.P., Burge C.B. Prediction of mammalian microRNA targets. Cell. 2003;115:787–798. PubMed

Krek A., Grun D., Poy M.N., Wolf R., Rosenberg L., Epstein E.J. Combinatorial microRNA target predictions. Nat. Genet. 2005;37:495–500. PubMed

Griffiths-Jones S., Grocock R.J., van A., Bateman D.S., Enright A.J. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 2006;34:D140–D144. PubMed PMC

Klimenko O.V. 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) 2017;3:1–8.

Klimenko O.V. Complex of small non-coding RNAs piR-30074 and Antago-miR-155 and miR-125b with DDMC carrier transforms girardi heart cells into CD4+ cells. J. Cancer Tumor. Int. 2016;4:1–8.

Klimenko O.V., Shtilman M.I. Transfection of Kasumi-1 cells with a new type of polymer carriers loaded with miR-155 and antago-miR-155. Cancer Gene Ther. 2013;20:237–241. PubMed

Torchilin V.P., Levchenko T.S., Whiteman K.R., Yaroslavov A.A., Tsatsakis A.M., Rizos A.K., Michailova E.V., Shtilman M.I. Amphiphilic poly-N-vinylpyrrolidones: synthesis, properties and liposome surface modification. Biomaterials. 2001;22:3035–3044. PubMed

Rizos A.K., Tsikalis I., Tsatsakis A.M., Shtilman M.I. Characterization of amphiphilic poly-N-vinylpyrrolidone derivatives by dynamic light scattering. J. Non-Crystall. Solids. 2006;352:5055–5059.

Kuskov A.N., Shtilman M.I., Goryachaya A.V., ashmuhamedov R.I.T., Yaroslavov A.A., Torchilin V.P., Tsatsakis A.M., Rizos A.K. Self-assembling nanoscaled drug delivery systems composed of amphiphilic poly-N-vinylpyrrolidones. J. Non-Crystall. Solids. 2007;353:3969–3975.

Kuskov A.N., Villemson A.L., Larionova N.I., Tsatsakis A.M., Shtilman M.I. Amphiphilic poly-N-vinylpyrrolidone nanocarriers with incorporated model proteins. J. Phys.: Condens. Mater. 2007;19:459–468.

Kuskov A.N., Voskresenskaya A.A., Goryachaya A.V., Artyukhov A.A., Shtilman M.I., Tsatsakis A.M. Preparation and characterization of amphiphilic poly-N-vinylpyrrolidone nanoparticles containing indomethacin. J. Mater. Sci.: Mater. Med. 2010;21:1521–1530. PubMed

Luss A.L., Andersen C.L., Benito I.G., Marzo R.C., Medina Z.H., Rosenlund M.B., Romme S.B., Kulikov P.P., Pennisi C.P., Shtilman M.I., Gurevich L. Drug delivery platform based on amphiphilic Poly-N-Vinyl-2-Pyrrolidone: the role of size distribution in cellular uptake. Biophys. J. 2018;114:278–279. PubMed

Kuskov A.N., Voskresenskaya A.A., Goryachaya A.V., Shtilman M.I., Spandidos D.A., Rizos A.K., Tsatsakis A.M. Amphiphilic poly-N-vinylpyrrolidone nanoparticles as carriers for non-steroidal anti-inflammatory drugs: characterization and in vitro controlled release of indomethacin. Int. J. Mol. Med. 2010;26:85–94. PubMed

Kuskov A.N., Kulikov P.P., Shtilman M.I., Rakitskii V.N., Tsatsakis A.M. Amphiphilic poly-N-vynilpyrrolidone nanoparticles: cytotoxicity and acute toxicity study. Food Chem. Toxicol. 2016;96:273–279. PubMed

Kuskov A.N., Kulikov P.P., Goryachaya A.V., Tzatzarakis M., Docea A.O., Velonia K., Shtilman M.I., Tsatsakis A.M. Amphiphilic poly-N-vinylpyrrolidonee nanoparticles as carriers for nonsteroidal, anti-inflammatory drugs: in vitro cytotoxicity and in vivo acute toxicity study, Nanomedicine: nanotechnology. Biol. Med. 2017;13:1021–1030. PubMed

Basak E., Neagu M., Nikitovich D., Henrich-Noack P., Docea A., Shtilman M., Golokhvast K., Tsatsakis A. Mechanistic understanding of nanoparticles’ interactions with extracellular matrix: the cell and immune system Ayse. Part. Fibre Toxicol. 2017;14:22–28. PubMed PMC

Kuskov A.N., Kulikov P.P., Goryachaya A.V., Tsatzarakis M.N., Tsatsakis A.M., Velonia K., Shtilman M.I. Self-assembled amphiphilic poly-N-vinylpyrrolidone nanoparticles as carriers for hydrophobic drugs: stability aspects. J. Appl. Polym. Sci. 2018;135:45673.

Shcherbo E.M., Merzlyak T.V., Chepurnykh A.F., Fradkov G.V., Ermakova E.A. Solovieva. Bright far-red fluorescent protein for whole body imaging. Nat. Methods. 2007;4:741–746. PubMed

Guo S.-L., Peng Z., Yang X., Fan K.-J., Ye H., Li Z.-H. miR-148a promoted cell proliferation by targeting p27 in gastric cancer cells. Int. J. Biol. Sci. 2011;7:567–574. PubMed PMC

Zhang H., Li Y., Huang Q., Ren X., Hu H., Sheng H. MiR-148a promotes apoptosis by targeting Bcl-2 in colorectal cancer. Cell Death Differ. 2011;18:1702–1710. PubMed PMC

Palmqvist R., Sellberg P., Oberg A., Tavelin B., Rutegard J.N., Stenling R. Low tumour cell proliferation at the invasive margin is associated with a poor prognosis in Dukes’ stage B colorectal cancers. Br. J. Cancer. 1999;79:577–581. PubMed PMC

Kimura T., Tanaka S., Haruma K., Sumii K., Kajiyama G., Shimamoto F. Clinical significance of MUC1 and E-cadherin expression, cellular proliferation, and angiogenesis at the deepest invasive portion of colorectal cancer. Int. J. Oncol. 2000;16:55–64. PubMed

Allegra C.J., Paik S., Colangelo L.H., Parr A.L., Kirsch I., Kim G. Prognostic value of thymidylate synthase, Ki-67, and p53 in patients with Dukes’ B and C colon cancer: a National Cancer institute-National Surgical Adjuvant Breast and Bowel Project collaborative study. J. Clin. Oncol. 2003;21:241–250. PubMed

Fluge Q., Gravdal K., Carlsen E., Vonen B., Kjellevold K., Refsum S. Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis. Br. J. Cancer. 2009;101:1282–1289. PubMed PMC

Matsubara S., Ding Q., Miyazaki Y., Kuwahata T., Tsukasa K., Takao S. mTOR plays critical roles in pancreatic cancer stem cells through specific and stemness-related functions. Sci. Rep. 2013;3:3230. PubMed PMC

Abbas A.K., Lichtman A.H., Pillai S. Cellular and Molecular Immunology. 6-E. Elsevier Inc.; 2007. Lymphocyte development and the rearrangement and expression of antigen receptor genes; p. 177.

Bagga S., Bracht J., Hunter S., Massier K., Holtz J., Eachus R. Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell. 2005;122:553–563. PubMed

Lytle J.R., Yario T.A., Steitz J.A. Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5’UTR as in the 3’UTR. PNAS. 2007;104:9667–9672. PubMed PMC

Folco H.D., Pidoux A.L., Urano T., Allshire R.C. Heterochromatin and RNAi are required to establish CENP-A chromatin at centromeres. Science. 2008;319:94–97. PubMed PMC

Tay Y., Zhang J., Thomson A.M., Lim B., Rigoutsos I. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature. 2008;455:1124–1128. PubMed

Varambally S., Cao Q., Mani R.S., Shankar S., Wang X., Ateeq B. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science. 2008;322:1695–1699. PubMed PMC

Hanna J., Saha K., Pando B., van Zon J., Lengner C.J., Creyghton M.P., van Oudenaarden A., Jaenisch R. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature. 2009;462:595–601. PubMed PMC

Cox D.N., Chao A., Baker J., Chang L., Qiao D., Lin H. A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal. Genes Dev. 2008;12:3715–3727. PubMed PMC

Cox D.N., Chao A., Lin H. Piwi encodes a nucleoplasmic factor whose activity modulates the number and division rate of germline stem cells. Development. 2000;127:503–514. PubMed

Yang C., Su H., Liao X., Han C., Yu T., Zhu G., Wang X., Winkler C.A., O’Brien S.J., Peng T. Marker of proliferation Ki-67 expression is associated with transforming growth factor beta 1 and can predict the prognosis of patients with hepatic B virus-related hepatocellular carcinoma. Cancer Manag. Res. 2018;10:679–696. PubMed PMC

Zhao L., Chen H., Hu B., Zhang H., Lin Q. Prognostic significance of Ki67 expression and the derived neutrophil-lymphocyte ratio in nasopharyngeal carcinoma. Cancer Manag. Res. 2018;10:1919–1926. PubMed PMC

Miller L., Min M., Yang C., Tian C., Gookin S., Carter D., Spencer S.L. Ki67 is graded rather than a binary marker of proliferation versus quiescence. Cell Rep. 2018;24:1105–1112. PubMed PMC

Grivna S.T., Pyhtila B., Lin H. MIWI associates with translational machinery and PIWI-interacting RNAs (piRNAs) in regulating spermatogenesis. PNAS. 2006;103:13415–13420. PubMed PMC

Grivna S.T., Beyret E., Wang Z., Lin H. A novel class of small RNAs in mouse spermatogenic cells. Genes Dev. 2006;20:1709–1714. PubMed PMC

Chen Y., Song Y.-X., Wang Z.-N. The microRNA-148/152 family: multi-faceted players. Mol. Cancer. 2013;12:43–51. PubMed PMC

Guan Z., Song B., Liu F., Sun D., Wang K., Qu H. TGF-b induces HLA-G expression through inhibiting miR-152 in gastric cancer cells. J. Biomed. Sci. 2015;22:107–113. PubMed PMC

Dang Y.W., Zeng J., He R.Q., Rong M.H., Luo D.Z., Chen G. Effects of miR-152 on cell growth inhibition, motility suppression and apoptosis induction in hepatocellular carcinoma cells. Asian Pac. J. Cancer Prev. 2014;15:4969–4976. PubMed

Cheng Z., Ma R., Tan W., Zhang L. MiR-152 suppresses the proliferation and invasion of NSCLC cells by inhibiting FGF2. Exp. Mol. Med. 2014;46:e112–e120. PubMed PMC

Takahashi M., Cuatrecasas M., Balaguer F., Hur K., Toiyama Yu., Castells A. The clinical significance of miR-148a as predictive biomarker in patients with advanced colorectal cancer. PLoS One. 2012;7 PubMed PMC

Peschansky V.J., Wahlestedt C. Non-coding RNAs as direct and indirect modulators of epigenetic regulation. Epigenetics. 2014;9:3–12. PubMed PMC

Meller V.H., Joshi S.S., Deshpande N. Modulation of chromatin by noncoding RNA. Annu. Rev. Genet. 2015;49:673–695. PubMed

Gaspar-Maia A., Alajem A., Meshorer E., Ramalho-Santos M. Open chromatin in pluripotency and reprogramming. Nat. Rev. Mol. Cell Biol. 2011;12:36–47. PubMed PMC

Singhal N., Graumann J., Wu G., Arauzo-Bravo M.J., Han D.W., Greber B. Chromatin-remodeling components of the BAF complex facilitate reprogramming. Cell. 2010;141:943–955. PubMed

Kuramochi-Miyagawa S., Kimura T., Ijiri T.W., Isobe T., Asada N., Fujita Y. Mili, a mammalian member of piwi family gene, is essential for spermatogenesis. Development. 2004;131:839–849. PubMed

Carmell M.A., Girard A., van de Kant H.J., Bourc’his D., Bestor T.H., deRooij D.G. MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. Dev. Cell. 2007;12:503–514. PubMed

Klattenhoff C., Bratu D.P., McGinnis-Schultz N., Koppetsch B.S., Cook H.A., Theurkauf W.E. Drosopilarasi RNA pathway mutations disrupt embryonic axis specification through activation of an ATR/Chk2 DNA damage response. Dev. Cell. 2007;12:45–55. PubMed

Lau N.C., Seto A.G., Kim J., Kuramochi-Miyagawa S., Nakano T., Barte D.P. Characterisation of the piRNA complex from rat testes. Science. 2006;313:363–367. PubMed

Whangbo J.S., Hunter C.P. Environmental RNA interference. Trends Genet. 2008;24:297–305. PubMed

Robert V.J., Davis M.W., Jorgensen E.M., Bessereau J.-L. Gene conversion and End-Joining-Repair double-strand breaks in the Caenorhabditis elegans germline. Genetics. 2008;180:673–679. PubMed PMC

Wang Q.E., Han C., Milum K., Wani A.A. Stem cell protein Piwil2 modulates chromatin modifications upon cisplatin treatment. Mutat. Res. 2011;708:59–68. PubMed PMC

Ishizu H., Siomi H., Siomi M.C. Biology of PIWI-interacting RNAs: new insights into biogenesis and function inside and outside of germlines. Genes Dev. 2012;26:2361–2373. PubMed PMC

Wang Y., Sun T., Wang K., Wang J.-X., Li P.F. PiRNAs link epigenetic modifications to reprogramming. Histol. Histopathol. 2014;29:1–9. PubMed

Moyano M., Giovanni S. piRNA involvement in genome stability and human cancer. J. Hematol. Oncol. 2015;8:38. PubMed PMC

Heneghan H.M., Miller N., Lowery A.J., Sweeney K.J., Newell J., Kerin M.J. Circulating microRNAs as novel minimally invasive biomarkers for breast cancer. Ann. Surg. 2010;251:499–505. PubMed

Brennecke J., Aravin A.A., Stark A., Dus M., Kellis M., Sachidanandam R. Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell. 2007;128:1089–1103. PubMed

Gunawardane S., Saito K., Nishida K.M., Miyoshi K., Kawamura Y., Nagami T. A slicer-mediated mechanism for repeat-associated siRNA 5′ end formation in Drosophila. Science. 2007;315:1587–1590. PubMed

Ahmadzada T., Reid G., McKenzie D.R. Fundamentals of siRNA and miRNA therapeutics and a review of targeted nanoparticle delivery systems in breast cancer. Biophys. Rev. 2018;10:69–86. PubMed PMC

Chakraborty C., Sharma A.R.G., Sarkar B.K., Lee S.-S. The novel strategies for next-generation cancer treatment: miRNA combined with chemotherapeutic agents for the treatment of cancer. Oncotarget. 2018;9:10164–10174. PubMed PMC

Chakraborty C., Sharma A.R., Sharma G., Doss C.G.P., Lee S.-S. Therapeutic miRNA and siRNA: moving from bench to clinic as next generation medicine. Mol. Ther. Nucleic Acids. 2017;8:132–143. PubMed PMC

Chalbatani G.M., Dana H., Memari F., Gharagozolou E., Ashjaei S., Kheirandish P., Marmari V., Mahmoudzadeh H., Maleki A.R., Sadeghian E., Nia E.Z., Miri S.R., Nia N.Z., Rezaeian O., Eskandary A., Razavi N., hirkhoda M., Rouzbahani F.N. Biological function and molecular mechanism of piRNA in cancer. Pract. Lab. Med. 2018;7(December) PubMed PMC

The full recovery of mice (Mus Musculus C57BL/6 strain) from virus-induced sarcoma after treatment with a complex of DDMC delivery system and sncRNAs