BACKGROUND: Virus-induced cellular genetic modifications result in the development of many human cancers. METHODS: In our experiments, we used the RVP3 cell line, which produce primary mouse virus-induced sarcoma in 100% of cases. Inbreed 4-week-old female C57BL/6 mice were injected subcutaneously in the interscapular region with RVP3 cells. Three groups of mice were used. For treatment, one and/or two intravenous injections of a complex of small non-coding RNAs (sncRNAs) a-miR-155, piR-30074, and miR-125b with a 2-diethylaminoethyl-dextran methyl methacrylate copolymer (DDMC) delivery system were used. The first group consisted of untreated animals (control). The second group was treated with one injection of complex DDMC/sncRNAs (1st group). The third group was treated with two injections of complex DDMC/sncRNAs (2nd group). The tumors were removed aseptically, freed of necrotic material, and used with spleen and lungs for subsequent RT-PCR and immunofluorescence experiments, or stained with Leishman-Romanowski dye. RESULTS: As a result, the mice fully recovered from virus-induced sarcoma after two treatments with a complex including the DDMC vector and a-miR-155, piR-30074, and miR-125b. In vitro studies showed genetic and morphological transformations of murine cancer cells after the injections. CONCLUSIONS: Treatment of virus-induced sarcoma of mice with a-miR-155, piR-30074, and miR-125b as active component of anti-cancer complex and DDMC vector as delivery system due to epigenetic-regulated transformation of cancer cells into cells with non-cancerous physiology and morphology and full recovery of disease.

SID ALEX GROUP Ltd Kyselova 1185 2 Prague 182 00 Czech Republic

See more in PubMed

Boccardo E., Villa L.L. Viral origin of human cancer. Curr. Med. Chem. 2007;14(24):2526–2539. PubMed

McLaughlin-Drubin, Munger K. Viruses associated with human cancer. Biochim. Biophys. Acta. 2008;1782(3):127–150. PubMed PMC

White M.K., Pagano J.S., Khalili K. Viruses and human cancers: a long road of discovery of molecular paradigms. Clin. Microbiol. Rev. 2014;27(3):463–481. PubMed PMC

Brower V. Connecting viruses to cancer: how research moves from association to causation. J. Natl. Cancer Inst. 2004;96(4):256–257. PubMed

Rous P. A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J. Exp. Med. 1911;13:397–411. PubMed PMC

Geryk J., Mazo A., Svoboda J., Hlozanek I. Replication of transformation-defective mutants of the Prague strain of Rous sarcoma virus and isolation of a td mutant from duck-adapted PR-RSV-C. Folia Biol (Praha) 1980;26(1):34–41. PubMed

Ahlstrom C.G., Forsby N. Sarcomas in hamsters after injection with Rous chicken tumor material. J. Exp. Med. 1962;115:839–852. PubMed PMC

Eidinoff M.L., Bates B., Steinglass M., Haddad J.R. Subcutaneous sarcomata in hamsters induced by Rous sarcoma virus (Bryan) Nat. 1965;208:336–338. PubMed

Svoboda J., Popovic M., Sainerova H., Mach O., Shoyab M., Baluda M.A. Incomplete viral genome in a non-virogenic mouse tumour cell line (RVP3) transformed by Prague strain of avian sarcoma virus. Int. J. Cancer. 1977;19:851–858. PubMed

Sudol M. From Rous sarcoma virus to plasminogen activator, src oncogene and cancer management. Oncogene. 2011;30:3003–3010. PubMed

Sen B., Johnson F.M. Regulation of Src family kinases in human cancers. J. Signal Transduct. 2011;2011:1–14. PubMed PMC

Rothschild S.I., Gautschi O. Src kinase inhibitors in the treatment of lung cancer: rationale and clinical data. Clin. Invest. 2012;2:387–396.

Gargalionis A.N., Karamouzis M.V., Papavassiliou A.G. The molecular rationale of Src inhibition in colorectal carcinomas. Int. J. Cancer. 2014;134:2019–2029. PubMed

Varkaris A., Katsiampoura A.D., Araujo J.C., Gallick G.E., Corn P.G. Src signaling pathways in prostate cancer. Cancer Metastasis Rev. 2014;33:595–606. PubMed PMC

Zhang S., Huang W.C., Zhang L., Lowery F.J., Ding Z., Guo H., Wang H., Huang S., Sahin A.A., Aldape K.D., Steeg P.S., Yu D. SRC family kinases as novel therapeutic targets to breast cancer brain metastases. Cancer Res. 2013;73:5764–5774. PubMed PMC

Leung Y.Y., Kuksa P.P., Amlie-Wolf A., Valladares O., Ungar L.H., Kannan S., Gregory B.D., Wang L.S. DASHR: database of small human noncoding RNAs. Nucleic Acids Res. 2016;44(Database issue):D216–D222. PubMed PMC

Romano G., Veneziano D., Acunzo M., Croce C.M. Small non-coding RNA and cancer. Carcinogenesis. 2017;38(5):485–491. PubMed PMC

Klimenko O.V., Onishi Y. The disappeared cancer cells 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.

Chan S.H., Wang L.H. Regulation of cancer metastasis by microRNAs. J. Biomed. Sci. 2015;22:9–20. PubMed PMC

Markopoulos G.S., Roupakia E., Tokamani M., Chavdoula E., Hatziapostolou M., Polytarchou C., Marcu K.B., Papavassiliou A.G., Sandaltzopoulos R., Kolettas E. A step-by-step microRNA guide to cancer development and metastasis. Cell. Oncol. 2017;40(4):303–339. PubMed

Ding X.M. MicroRNAs: regulators of cancer metastasis and epithelial-mesenchymal transition (EMT) Chin. J. Canc. 2014;33(3) 140-147; Ma L. MicroRNA and metastasis. Adv Cancer Res. 2016; 132: 165-207. PubMed PMC

Kim J., Yao F., Xiao Z., Sun Y., Ma L. MicroRNAs and metastasis: small RNAs play big roles. Cancer Metastasis Rev. 2018;37(1):5–15. PubMed PMC

Nambara S., Mimori K. MicroRNA in various aspects of cancer development. Gan To Kagaku Ryoho. 2017;44(5):362–366. PubMed

Lou W., Liu J., Gao Y., Zhong G., Chen D., Shen J., Bao C., Xu L., Pan J., Cheng J., Ding B., Fan W. MicroRNAs in canver metastasis and angiogenesis. Oncotarget. 2017;8(70):115787–115802. PubMed PMC

Jafri M.A., Al-Qahtani M.H., Shay J.W. Role of miRNAs in human cancer metastasis: implications for therapeutic intervention. Semiars Canc. Biol. 2017;44:117–131. PubMed

Oneyama C., Okada M. MicroRNAs as the fine-tuners of Src oncogenic signaling. J. Biochem. 2015;157(6):431–438. PubMed

Kokuda R., Watanabe R., Okuzaki D., Akamatsu H., Oneyama C. MicroRNA-137-mediated Src oncogenic signaling promotes cancer progression. Genes Cells. 2018;23(8):688–701. PubMed

Sani S., Arora S., Majid S., Shahryari V., Chen Y., Deng G., Yamamura S., Ueno K., Dahiya R. Curcumin modulates microRNA-203-mediated regulation of the Src-Akt axis in bladder cancer. Cancer Prev. Res. 2011;4(10):1698–1709. PubMed PMC

Liu Y.N., Yin J.J., Barret B., Sheppard-Tillman H., Li D., Casey O.M., Fang L., Hynes P.G., Ameri A.H., Kelly K. Loss of androgen-regulated microRNA-1 activates Src and promotes prostate cancer bone metastasis. Mol. Cell Biol. 2015;35(11):1940–1951. PubMed PMC

Majid S., Sani S., Dar A.A., Hirata H., Shahryari V., Tanaka Y., Yamamura S., Ueno K., Zaman M.S., Singh K., Chang I., Deng G., Dahiya R. MicroRNA-205 inhibits Src-mediated oncogenic pathways in renal cancer. Cancer Res. 2011;71(7):2611–2621. PubMed PMC

Sun V., Zhou W.B., Nosrati M., Majid S., Thummala S., de Semir D., Bezrookove V., de Feraudy S., Chun L., Schadendorf D., Debs R., Kasani-Sabet M., Dar A.A. Antitumor activity of miR-1280 in melanoma by regulation of Src. Mol. Ther. 2015;23(1):71–78. PubMed PMC

Wang N., Liang H., Zhou Y., Wang C., Zhang S., Pan Y., Wang Y., Yan X., Zhang J., Zhang C.Y., Zen K., Li D., Chen X. miR-203 suppresses the proliferation and migration and promotes the apoptosis of lung cancer cells by targeting Src. PLoS One. 2014;9(8) PubMed PMC

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. Canc. Gene Ther. 2013;20:237–241. PubMed

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. Canc. Tumor Int. 2016;4:1–8.

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;3:1–6.

Klimenko O.V., Shtilman M. Reprogramming of CaCo2 colorectal cancer cells after using the complex of poly-(N-vinylpyrrolidone) with small non-coding RNAs. Toxicology Rep. 2019 doi: 10.1016/j.toxrep.2019.02.001. PubMed DOI PMC

Svoboda J. Dependence among RNA-containing animal viruses. Symp. Soc. Gen. Microbiol. 1968;18:249–271.

Schwartz D.E., Tizard R., Gilbert W. Nucleotide sequence of Rous sarcoma virus. Cell. 1983;32:853–869. PubMed

Sainerova H., Svoboda J. Long-term karyological study of RVP3 tumor cells grown in vitro. Folia Biol. 1978;24:242–252. PubMed

Sainerova H., Svoboda J. Stability of C-banded and C-bandless microchromosomes in clonal sublines of the RVP3 mouse tumor grown serially in vivo. Cancer Genet. Cytogenet. 1981;3:93–99. PubMed

Stehelin D., Fujita D.J., Padgett T., Varmus H.E., Bishop J.M. Detection and enumeration of transformation-defective strains of avian sarcoma virus with molecular hybridization. Virology. 1977;76:675–684. PubMed

Rynditch A.V., Gerik I., Lgotak V., Yatsula B.A., Svoboda J. Absence of the avian sarcoma virus genes in the transformed mammalian cells. Bioplolymers Cell. 1985;1:92–98.

Bister K. Discovery of oncogenes: the advent of molecular cancer research. Proc. Natl. Acad. Sci. Unit. States Am. 2015;112:15259–15260. PubMed PMC

Rubin H. The early history of tumor virology: Rous, RIF, and RAV. Proc. Natl. Acad. Sci. Unit. States Am. 2011;108:14389–14396. PubMed PMC

Lewis S.M., Kumari S. Guidelines on standard operating procedures for hematology. WHO. 2000:41–47.

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. Combinatorial microRNA target predictions. Nat. Genet. 2005;37:495–500. PubMed

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

Klimenko O.V. The toxicity and transfection efficiency of new non-viral delivery systems for small non-coding RNAs: amphiphilic poly-N-vinylpyrrolidone and diethylaminoethyl–dextran–methacrylic acid methylester copolymer. Adv. Sci. Eng. Med. 2017;9:1–6.

Gorman C. High efficiency gene transfer into mammalian cells. In: Glover D.M., editor. DNA Cloning: A Practical Approach. second ed. IRL; Oxford: 1985. pp. 143–190.

Haas J., Park E.C., Seed B. Codon usage limitation in the expression of HIV-1 envelope glycoprotein. Curr. Biol. 1996;6:315–324. PubMed

Kozak M. An analysis of 5’-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 1987;15:8125–8148. PubMed PMC

Shcherbo D., Merzlyak E.M., Chepurnykh T.V., Fradkov A.F., Ermakova G.V., Solovieva E.A., Lukyanov K.A., Bogdanova E.A., Zaraisky A.G., Lukyanov S., Chudakov D.M. Bright far-red fluorescent protein for whole body imaging. Nat. Meth. 2007;4:741–746. PubMed

Physical, Methods: Gillesby R., Hill J., Woods J. AVMA.org.; 2013. AVMA Guidelines for the Euthanasia of Animals: 2013. Version 2013.0.1.

Martin G.S. The road to Src. Oncogene. 2004;23:7910–7917. PubMed

Weiss R.A., Vogt P.K. 100 years of Rous sarcoma virus. JEM. 2011;208:2351–2355. PubMed PMC

Svoboda J. Cell association in Rous sarcoma virus (RSV) rescue and cell infection. Folia Biol (Praha) 2015;61:161–167. PubMed

Varmus H.E., Bishop J.M., Vogt P.K. Appearance of virus-specific DNA in mammalian cells following transformation by Rous sarcoma virus. J. Mol. Biol. 1973 PubMed

Varmus H.E., Stavnezer J., Medeiros E., Bishop J.M. Detection and characterization of RNA tumor virus-specific DNA in cells. In: Ito Y., Dutcher R.M., editors. Comparative Leukemia Research. Leukemogenesis. University of Tokyo Press, Tokyo/Karger; Basel: 1975. p. 451. PubMed

Varmus H.E., Stehelin D., Spector D., Tal J., Fujita D., Padgett T., Rouland-Dussoix D., Kung H.J., Bishop J.M. Distribution and function of defined regions of avian tumor virus genomes in viruses and uninfected cells. ICN-UCLA Symp. Mol. Cell. Biol. 1976;4

Svoboda J., Vesely P., Vrba M., Jiranek L. Biological properties of rat cells transformed in vitro by Rous sarcoma virus. Folia Biol (Praha) 1965;11:251–257. PubMed

Plachy J., Hala K., Hejnar J., Geryk J., Svoboda J. Src-specific immunity in inbred chickens bearing v-src DNA- and RSV-induced tumors. Immunogenetics. 1994;40:257–265. PubMed

Plachy J., Hejnar J., Trtkova K., Trejbalova K., Svoboda J., Hala K. DNA vaccination against v-src oncogene - induced tumors in congenic chickens. Vaccine. 2001;19:4526–4535. PubMed

Svoboda J., Plachy J., Hejnar J., Karakoz I., Guntaka R.V., Geryk J. Tumor induction by the LTR, v-src, LTR DNA in four B (MHC) congenic lines of chickens. Immunogenetics. 1992;35:309–315. PubMed

Svoboda J., Plachy J., Hejnar J., Geryk J. Specific rejection immunity against src oncogene-induced tumors and involvement of the major histocompatibility complex. Folia Biol (Praha) 1996;42:41–45. PubMed

Dehm S.M., Bonham K. SRC gene expression in human cancer: the role transcriptional activation. Biochem. Cell Biol. 2004;82:263–274. PubMed

Irby R.B., Yeatman T.J. Role of Src expression and activation in human cancers. Oncogene. 2000;19:5636–5642. PubMed

Giglione C., Gonfloni S., Parmeggiani A. Differential actions of p60c-Src and Lck kinases on the Ras regulators p120-GAP and GDP/GTP exchange factor CDC25Mm. Eur. J. Biochem. 2001;268:3275–3283. PubMed

Sen B., Johnson F.M. Regulation of Src family kinases in human cancers. J. Signal Transduct. 2011;2011:865819. PubMed PMC

Puls L.N., Eadens M., Messersmith W. Current status of Src inhibitors in solid tumor malignancies. Oncology. 2011;16:566–578. PubMed PMC

Hill W.G., Kaetzel M.A., Kishore B.K., Dedman J.R., Zeidel M.L. Annexin A4 reduces water and proton permeability of model membranes but does not alter aquaporin 2-mediated water transport in isolated endosomes. J. Gen. Physiol. 2003;121:413–425. PubMed PMC

Sohma H., Creutz C.E., Gasa S., Ohkawa H., Akino T., Kuroki Y. Differential lipid specificities of the repeated domains of annexin IV. Biochim. Biophys. Acta. 2001;1546:205–215. PubMed

Piljic A., Schultz C. Annexin A4 self-association modulates general membrane protein mobility in living cells. Mol. Biol. Cell. 2006;17:3318–3328. PubMed PMC

Kaetzel M.A., Chan H.C., Dubinsky W.P., Dedman J.R., Nelson D.J. A role for annexin IV in epithelial cell function. Inhibition of calcium-activated chloride conductance. J. Biol. Chem. 1994;269:5297–5302. PubMed

Jeon Y.J., Kim D.H., Jung H., Chung S.J., Chi S.W., Cho S. Annexin A4 interacts with the NF-kappaB p50 subunit and modulates NF-kappa B transcriptional activity in a Ca2 + −dependent manner. Cell. Mol. Life Sci. 2010;67:2271–2281. PubMed PMC

Choi C.H., Chung J.-Y., Chung E.J., Sears J.D., Lee J.W., Bae D.-S., Hewitt S.M. Prognostic significance of annexin A2 and annexin A4 expression in patients with cervical cancer. BMC Canc. 2016;16:448. PubMed PMC

Willimott S., Wagner S.D. MiR-125b and miR-155 contribute to BCL2 repression and proliferation in response to CD40 ligand (CD154) in human leukemic B-cells. J. Biol. Chem. 2012;287:2608–2617. PubMed PMC

Hofmann M.H., Heinrich J., Radziwill G., Moelling K. A short hairpin DNA analogous to miR-125b inhibits C-Raf expression, proliferation, and survival of breast cancer cells. Mol. Canc. Res. 2009;7:1635–1644. PubMed

Le M.T., Teh C., Shyh-Chang N., Xie H., Zhou B., Korzh V., Lodish H.F., Lim B. MicroRNA-125b is a novel negative regulator of p53. Genes Dev. 2009;23:862–876. PubMed PMC

Scott G.K., Goga A., Bhaumik D., Berger C.E., Sullivan C.S., Benz C.C. Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b. J. Biol. Chem. 2007;282:1479–1486. PubMed

Ferracin M., Bassi C., Pedriali M., Pagotto S., D'Abundo L., Zagatti B., Corra F., Musa G., Callegari E., Lupini L., Volpato S., Querzoli P. miR-125b targets erythropoietin and its receptor and their expression correlates with metastatic potential and ERBB2/HER2 expression. Mol. Canc. 2013;12:130–141. PubMed PMC

Manfe V., Biskup E., Willumsgaard A., Skov A.G., Palmeri D., Gasparini P., Lagana A., Woetmann A., Odum N., Croce C.M., Gniadecki R. cMyc/miR-125b-5p signaling determines sensitivity to Bortezomib in preclinical model of cutaneous T-cell lymphomas. PLoS One. 2013;8(3) PubMed PMC

Wang B., Hsu S.H., Wang X., Kutay H., Bid H.K., Yu J., Ganju R., Jacob S., Yuneva M., Ghoshal K. Reciprocal regulation of miR-122 and c-Myc in hepatocellular cancer: role of E2F1 and TFDP2. Hepatology. 2014;59(2):555–566. PubMed PMC

Haghikia A., Hoch M., Stapel B., Hilfiker-Kleiner D. STAT3 regulation of and by microRNAs in development and disease. JAK-STAT. 2012;1(3):143–150. PubMed PMC

Feng J., Fan Y., Ayiheng Q., Zhang H., Yong J., Hu B. MicroRNA-125b targeted STAT3 to inhibit laryngeal squamous cell carcinoma cell growth and motility. Oncol. Lett. 2017;14(1):480–486. PubMed PMC

Liu L., Li H., Li J.P., Zhong H., Zhang H.C., Chen J., Xiao T. MiR-125b suppresses the proliferation and migration of osteosarcoma cells through down-regulation of STAT3. Biochem. Biophys. Res. Commun. 2011;416(1–2):31–38. PubMed

Higgs G., Slack F. The multiple roles of microRNA-155 in oncogenesis. J. Clin. Bioinform. 2013;3:17. PubMed PMC

Zuo J., Yu Y., Zhu M., Jing W., Yu M., Chai H., Liang C., Tu J. Inhibition of miR-155, a therapeutic target for breast cancer, prevented in cancer stem cell formation. Cancer Biomark. 2018;21(2):383–392. PubMed

Bayraktar R., Van Roosbroeck K. miR-155 in cancer drug resistance and as target for miRNA-based therapeutics. Cancer Metastasis Rev. 2018;37(1):33–44. PubMed

Van Roosbroeck K., Fanini F., Setoyama T., Ivan C., Rodriguez-Aguayo C., Fuentes-Mattei E., Xiao L., Vannini I., Redis R.S., D'Abundo L., Zhang X., Nicoloso M.S., Rossi S., Gonzalez-Villasana V., Rupaimoole R., Ferracin M., Morabito F., Neri A., Ruvolo P.P., Ruvolo V.R., Pecot C.V., Amadori D., Abruzzo L., Calin S., Wang X., You M.J., Ferrajoli A., Orlowski R., Plunkett W., Lichtenberg T.M., Davuluri R.V., Berindan-Neagoe I., Negrini M., Wistuba I.I., Kantarjian H.M., Sood A.K., Lopez-Berestein G., Keating M.J., Fabbri M., Calin G.A. Combining anti-miR-155 with chemotherapy for the treatment of lung cancers. Clin. Cancer Res. 2017;23(11):2891–2904. PubMed PMC

Lin Q., Ma L., Wang D., Yang Z., Wang J., Liu Z., Jiang G. A novel camptothecin analogue inhibits colon cancer development and downregulates the expression of miR-155 in vivo and in vitro. Transl. Cancer Res. 2017;6(3):511–520.

Baba O., Hasegawa S., Nagai H. Micro-RNA-155-5p is associated with oral squamous cell carcinoma metastasis and poor prognosis. J. Oral Pathol. Med. 2016;45:248–255. PubMed

Lei K., Du W., Lin S. 3B, a novel photosensitizer, inhibits glycolysis and inflammation via miR-155-5p and breaks the JAK/STAT3/SOCS1 feedback loop in human breast cancer cells. Biomed. Pharmacother. 2016;82:141–150. PubMed

Wang X., Chen Z. Micro-RNA-19a functions as an oncogenic microRNA in non-small cell lung cancer by targeting the suppressor of cytokine signaling and mediating STAT3 activation. Int. J. Mol. Med. 2015;35:839–846. PubMed

Huang C., Li H., Wu W., Jiang T., Qiu Z. Regulation of miR-155 affects pancreatic cancer cell invasiveness and migration by modulating the STAT3 signaling pathway through SOCS1. Oncol. Rep. 2013;30:1223–1230. PubMed

Kobayashi N., Uemura H., Nagahama K. Identification of miR-30d as novel prognostic marker of prostate cancer. Oncotarget. 2012;3:1455–1471. PubMed PMC

Shen R., Wang Y., Wang C.X. MiRNA-155 mediates TAM resistance by modulating SOCS6-STAT3 signaling pathway in breast cancer. Am. J. Transl. Res. 2015;7:2115–2126. PubMed PMC

Zhang L., Li J., Wang Q., Meng G., Lv X., Zhou H., Li W., Zhang J. The relationship between microRNAs and the STAT3-related signaling pathway in cancer. Tumor Biol. 2017;39(7):1–11. PubMed

Cao H., Huang Sh, Liu A., Chen Z. Up-regulated expression of miR-155 in human colonic cancer. J. Cancer Res. Ther. 2018;14(3):604–607. PubMed

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

Ayarpadikannan S., Kim H.-S. The impact of transposable elements in genome evolution and genetic instability and their implications in various diseases. Genom. Inform. 2014;12(3):98–104. PubMed PMC

Loreto E.L.S., Pereira C.M. Somatizing the transposons action. Mobile Genet. Elem. 2017;7(3):1–9. PubMed PMC

Anwar S.L., Wulaningsih W., Lehmann U. Transposable elements in human cancer: causes and consequences of deregulation. Int. J. Mol. Sci. 2017;18:974–995. PubMed PMC

Burns K.H. Transposable elements in cancer. Nat. Rev. Canc. 2017;17:415–424. Chenais B. Transposable elements in cancer and other human diseases. Curr Cancer Drug Targets 2015; 15(3): 227-42. PubMed

Chenais B. Transposable elements and human cancer: a causal relationship? BBA: Revisiones Cáncer. 2013;1835(1):28–35. PubMed

Akash M.S.H., Usman M., Qadir M.I. Transposable elements (human endogenous retroviruses) in cancer. Crit. Rev. Eukaryot. Gene Expr. 2017;27(3):219–227. PubMed

Thomas A.L., Rogers A.K., Webster A., Marinov G.K., Liao S.E., Perkins E.M., Hur J.K., Aravin A.A., Toth K.F. Piwi induces piRNA-guided transcriptional silencing and establishment of a repressive chromatin state. Genes Dev. 2013;27(4):390–399. PubMed PMC

Czech B., Hannon G.J. One loop to rule them all: the ping-pong cycle and piRNA-guided silencing. Trends Biochem. Sci. 2016;41(4):324–337. PubMed PMC

Chen Y.-C.A., Stuwe E., Luo Y., Lipshitz H.D., Toth K.F., Aravin A.A. Cutoff suppresses RNA polymerase II termination to ensure of piRNA precursors. Mol. Cell. 2016;63:97–109. PubMed PMC

Beltran T., Barroso C., Birkle T.Y., Martinez-Perez E., Blaxter M., Sarkies P. Comparative epigenomics reveals that RNA polymerase II pausing and chromatin domain organization control nematode piRNA biogenesis. Dev. Cell. 2019;48:1–18. PubMed PMC

Huang X.A., Yin H., Sweeney S., Raha D., Snyder M., Lin H. A major epigenetic programming mechanism guided by piRNAs. Dev. Cell. 2013;24(5):502–516. PubMed PMC

Ng K.W., Anderson C., Marshall E.A., Minatel B.C., Enfield K.S.S., Saprunov H.L., Lam W.L., Martinez V.D. PIWI-interacting RNAs in cancer: emerging functions and clinical utility. Mol. Canc. 2016;15:5–19. PubMed PMC

Huang G., Hu H., Xue X., Shen S., Gao E., Guo G. Altered expression of piRNAs and their relation with clinicopathologic features of breast cancer. Clin. Transl. Oncol. 2013;15(7):563–568. PubMed

Yin J., Qi W., Ji C., Xie X.-L., Wang C., Chen L., Jiang H. Sa1979 the role of piRNA-823 in human colorectal cancer: from deep sequencing analysis to functional validation. Gaestroenterology. 2015;148(4) S-373.

Chu H., Xia L., Qiu X., Gu D., Zhu L., Jin J., Hui G., Hua Q., Du M., Tong N., Chen J., Zhang Z., Wang M. Genetic variants in noncoding PIWI-interacting RNA and colorectal cancer risk: piRNA SNPs and colorectal cancer risk. Cancer. 2015;121(12):2044–2052. PubMed

Weng W., Liu N., Toiyama Y., Kusunoki M., Nagasaka T., Fujiwara T., Wei Q., Qin H., Lin H., Ma Y., Goel A. Novel evidence for a PIWI-interacting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer. Mol. Canc. 2018;17(1):16. PubMed PMC

Han Y.-N., Li Y., Xia S.-Q., Zhang Y.-Y., Zheng J.-H., Li W. PIWI proteins and PIWI-interacting RNA: emerging roles in cancer. Cell. Physiol. Biochem. 2017;44:1–20. PubMed

Zhang S.-J., Yao J., Shen B.-Z., Li G.-B., Kong S.-S., Bi D.-D., Pan S.-H., Cheng B.-L. Role of piwi-interacting RNA-651 in the carcinogenesis of non-small cell lung cancer. Oncol. Lett. 2018;15(1):940–946. PubMed PMC

Chalbatani G.M., Dana H., Memari F., Gharagozlou E., Ashjaei S., Kheirandish P., Marmari V., Mahmoudzadeh H., Mozayani F., Maleki A.R., Sadeghian E., Nia E.Z., Miri S.R., Nia N.z., Rezaeian O., Eskandary A., Razavi N., Shirkhoda M., Rouzbahani F.N. Biological function and molecular mechanism of piRNA in cancer. Pract. Lab. Med. 2018;13 PubMed PMC

He X., Chen X., Zhang X., Duan X., Pan T., Hu Q., Zhang Y., Zhong F., Liu J., Zhang H., Luo J., Wu K., Peng G., Luo H., zhang L., Li X., Zhang H. An Lnc RNA (GAS5)/SnoRNA-derived piRNA induces activation of TRAIL gene by site-specifically recruiting MLL/COMPASS-like complexes. Nucleic Acids Res. 2015;43(7):3712–3725. PubMed PMC

Mei Y., Wang Y., Kumari P., Shetty A.C., Clarck D., Gable T., MacKerell A.D., Ma M.Z., Weber D.J., Yang A.J., Edelman M.J., Mao L. A piRNA-like small RNA interacts with and modulates p-ERM proteins in human somatic cells. Nat. Commun. 2015;6:7316. PubMed PMC

Assumpcao C.B., Calcagno D.Q., Araujo T.M.T., Batista dos Santos E., dos Santos A.K.C.R., Riggins G.J., Burbano R.R., Assumpcao P.P. The role of piRNA and its potential clinical implications in cancer. Epigenomics. 2015;7(6):975–984. PubMed PMC

Yao Y., Li C., Zhou X., Zhang Y., Lu Y., Chen J., Zheng X., Tao D., Liu Y., Ma Y. PIWIL2 induces c-Myc expression by interacting with NME2 and regulates c-Myc-mediated tumor cell proliferation. Oncotarget. 2014;5(18):8466–8477. PubMed PMC

Mai D., Ding P., Tan L., Zhang J., Pan Z., Bai R., Li C., Zhou Y., Tan W., Zhou Z., Li Y., Zhou A., Ye Y., Pan L., Zheng Y., Su J., Zuo Z., Liu Z., Zhao Q., Li X., Huang X., Li W., Wu S., Jia W., Zou S., Wu C., Xu R., Zheng J., Lin D. PIWI-interacting RNA-54265 is oncogenic and potential therapeutic target in colorectal adenocarcinoma. Theranostics. 2018;8(19):5213–5230. PubMed PMC

Jacobs D.I., Qin Q., Fu A., Chen Z., Zhou J., Zhu Y. piRNA-8041 is downregulated in human glioblastoma and suppresses tumor growth in vitro and in vivo. Oncotarget. 2018;9(102):37616–37626. PubMed PMC

Perspectives on the Use of Small Noncoding RNAs as a Therapy for Severe Virus-Induced Disease Manifestations and Late Complications