稿を終えるにあたり、懇篤なる御指導、御高閲を頂きました、福岡大学 薬学部 統合臨床医学講座 免疫・分子治療学分野 中島 学 教授に深甚なる感謝の意を 表します。また、今回このような機会を与えて下さった九州大学大学院歯学研究院 口腔顎顔面病態学講座 顎顔面腫瘍制御学分野 中村 誠司 教授に深甚なる感謝 の意を表します。直接御指導いただき、すべての研究遂行、および本稿と投稿論文 の作成に際し懇切丁寧な御指導、御助言を頂きました福岡大学 薬学部 統合臨床 医学講座 免疫・分子治療学分野 安河内（川久保） 友世 講師に深甚なる感謝の意 を表します。その他の各種実験に際し様々な御指導、御助言を頂きました福岡大学 薬学部 統合臨床医学講座 免疫・分子治療学分野の皆様に深謝いたします。大学 院入学時より様々な御助言を頂きました九州大学大学院歯学研究院 口腔顎顔面 病態学講座 顎顔面腫瘍制御学分野の皆様に深謝いたします。
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参 考
文 献
1. Kucharzewska P, Christianson HC, Welch JE, Svensson KJ, Fredlund E, Ringnér M, Mörgelin M, Bourseau-Guilmain E, Bengzon J, Belting M. Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci USA 2013;110:
7312–7317.
2. Kosaka N, Iguchi H, Hagiwara K, Yoshioka Y, Takeshita F, Ochiya T. Neutral sphingomyelinase2 (nSMase2)-dependent exosomal transfer of angiogenic
microRNAs regulate cancer cell metastasis. J Biol Chem 2013;288(15):10849–
10859.
3. Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 1987;262(19):9412–9420.
4. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO.
Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007;9:654–659.
5. Huang Q, Gumireddy K, Schrier M, Ie Sage C, Nagel R, Nair S, Egan DA, Li A, Huang G, Klein-Szanto AJ, Gimotty PA, Katsaros D, Coukos G, Zhang L, Puré E, Agami R. The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nat Cell Biol 2008;10:202–210.
6. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar C, Nitadori- Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan J, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang Y, Bromberg J, Lyden D. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 2012;18:883–891.
7. Harris DA, Patel SH, Gucek M, Hendrix A, Westbroek W, Taraska JW.
Exosomes released from breast cancer carcinomas stimulate cell movement.
PLoS One 2015;10:e0117495.
8. Atay S, Banskota S, Crow J, Sethi G, Rink L, Godwin AK. Oncogenic KIT- containing exosomes increase gastrointestinal stromal tumor cell invasion. Proc Natl Acad Sci USA 2014;111:711–716.
9. Kapsogeorgou EK, Abu-Helu RF, Moutsopoulos HM. Salivary gland epithelial cell exosomes: A source of autoantigenic ribonucleoproteins. Arthritis &
Rheumatism 2005;52(5):1517–1521.
49
10. Valadi H, Ekstrom K, Bossios A, Lötvall JO. Exosome- mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 2007;9(6):654–659.
11. Morifuji M, Taniguchi S, Sakai H, Nakabeppu Y, Ohishi M. Differential expression of cytokeratin after orthotopic implantation of newly established human tongue cancer cell lines of defined metastatic ability. Am J Pathol 2000;156(4):1317–1326.
12. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009;136:215–223.
13. Chekulaeva M, Filipowicz W. Mechanisms of miRNA-mediated post-transcriptional regulation in animal cells. Curr Opin Cell Biol Biol 2009;21:452–460.
14. Jansson MD, Lund AH. MicroRNA and cancer. Mol Oncol 2012;6:590-610.
15. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer 2006;6:857–866.
16. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thausands of human genes are microRNA targets. Cell 2005;120:1-20.
17. Grimson A, Farh KK, Johnston WK, Garrett-Engele P, Lim LP, Bartel DP.
MicroRNA targeting specificity in mammals: determinants beyond seed pairing.
Mol Cell 2007;27:91–105.
18. Chou CH, Chang NW, Shrestha S, Hsu SD, Lin YL, Lee WH, Yang CD, Hong HC, Wei TY, Tu SJ, Tsai TR, Ho SY, Jian TY, Wu HY, Chen PR, Lin NC, Huang HT, Yang TL, Pai CY, Tai CS, Chen WL, Huang CY, Liu CC, Weng SL, Liao KW, Hsu WL, Huang HD. miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database. Nucleic Acids Res 2016;44:D239–
D247.
19. Berezikov E, Guryev V, van de Belt J, Wienholds E, Plasterk RH, Cuppen E.
Phylogenetic shadowing and computational identification of human microRNA genes. Cell 2005;120:21–24.
20. De Cola A, Volpe S, Budani MC, Ferracin M, Lattanzio R, Turdo A, D'Agostino D, Capone E, Stassi G, Todaro M, Di Ilio C, Sala G, Piantelli M, Negrini M, Veronese A, De Laurenzi V. miR-205-5p-mediated downregulation of ErbB/HER receptors in breast cancer stem cells results in targeted therapy resistance. Cell Death Dis 2015;6:e1823.
50
21. Johnson JJ, Miller DL, Jiang R, Lui Y, Shi Z, Tarwater L, Williams R, Balsara R, Sauter ER, Stack MS. Protease-activated receptor-2-mediated NF-κB activation suppresses inflammation-associated tumor suppressor microRNA in oral squamous cell carcinoma. J Biol Chem 2016;291:6936–6945.
22. Wong CM, Wei L, Au SL, Fan DN, Zhou Y, Tsang FH, Law CT1, Lee JM, He X, Shi J, Wong CC, Ng IO. MiR-200b/200c/429 subfamily negatively regulates Rho/ROCK signaling pathway to suppress hepatocellular carcinoma metastasis.
Oncotarget 2015;6:13658–13670.
23. Hur K, Toiyama Y, Takahashi M, Balaguer F, Nagasaka T, Koike J, Hemmi H, Koi M, Boland CR, Goel A. MicroRNA-200c modulates epithelial-to mesenchymal transition (EMT) in human colorectal cancer metastasis. Gut 2013;62:1315–1326.
24. Li H, Xu L, Li C, Zhao L, Ma Y, Zheng H, Li Z, Zheng Y, Wang R, Liu Y, Qu X.
Ubiquitin ligase Cbl-b represses IGF-induced epithelial mesenchymal transition via ZEB2 and microRNA-200c regulation in gastric cancer cells. Mol Cancer 2014;13:136.
25. Lo WL, Yu CC, Chiou GY, Chen YW, Huang PI, Chien CS, Tseng LM, Chu PY, Lu KH, Chang KW, Kao SY, Chiou SH. MicroRNA-200c attenuates tumor growth and metastasis of presumptive head and neck squamous cell carcinoma stem cells. J Pathol 2011;223:482–495.
26. Zhang HP, Sun FB, Li SJ. Serum miR-200c expression level as a prognostic biomarker for gastric cancer. Genet Mol Res 2015;14:15913–15920.
27. Meng X, Muller V, Milde-Langosch K, Trillsch F, Pantel K, Schwarzenbach H.
Circulating cell-free miR-373, miR-200a, miR-200b, and miR-200c in patients with epithelial ovarian cancer. Adv Exp Med Biol 2016;924:3–8.
28. Le MT, Hamar P, Guo C, Basar E, Perdigao-Henriques R, Balaj L, Lieberman J.
miR-200-containing extraccelur vesicles promote breast cancer cell metastasis. J Clin Invest 2014;124:5109–5128.
29. Hall JA, Georgel PT. CHD protein: a diverse family with strong ties. Biochem Cell Biol 2007;85:463–376.
30. Lasorsa VA, Formicola D, Pignataro P, Cimmino FM, Mora J, Esposito MR, Pantile M, Zanon C, De Mariano M, Longo L, Hogarty MD, De Torres C, Tonini GP, Iolascon A, Capasso M. Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathway involved in cancer prognosis. Oncotarget 2016;7:21840–21852.
51
31. Orlovetskie N, Serruya R, Abboud-Jarrous G, Jarrous N. Targeted inhibition of WRN helicase, replication stress and cancer. Biochem Biophys Acta 2017;1867:42–48.
32. Futami K, Furuichi Y. RECQL1 and WRN DNA repair helicases: potential therapeutic targets and proliferative markers against cancers. Front Genet 2015;5:441.
33. Hickson ID. RecQ helicases: caretakers of the genome. Nat Rev Cancer 2003;3:169–178.
34. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86(3):353-364.
35. Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Ylä-Herttuala S, Jäättelä M, Alitalo K. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 2001;61(5):
1786–1790.
36. Liang Z, Brooks J, Willard M, Liang K, Yoon Y, Kang S, Shim H.
CXCR4/CXCR12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway. Biochem Biophys Res Commun 2007;359:716–22.
37. Seo M, Choi JS, Rho CR, Joo CK, Lee SK. MicroRNA miR-466 inhibits lymphangiogenesis by targeting prospero-related homeobox 1 in the alkali burn corneal injury model. J Biomed Sci. 2015;22:3.
38. Ferrara N, Gerber HP, Le Couter J. The biology of VEGF and its receptors. Nat Med 2003;9:669–76.
39. Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol 2009;21:154–165.
40. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor.
Endocrine Rev 1997;18:4–25.
41. Shibuya m, Ito N, Claesson-Welsh L. Structure and function of VEGF Receptor-1 and -2. Curr Top Micro Immunol 1999;237:59–83.
42. Alitalo K, Tammela T, Petrova TV. Lymphangiogenesis in development and human disease. Nature 2005;438:946–953.
43. Rodriguez-Fraticelli AE et al. Divide and polarize: recent advances in the molecular mechanism regulating epithelial tubulogenesis, Curr Opin Cell Biol 2011;23:638–646.
44. Sucharov C, Bristow MR, Port JD. miRNA expression in the failing human heart:
Functional correlates. J Mol Cell Cardiol 2008;45(2):185–192.