Micrornas in breastmilk and the lactating breast: Potential immunoprotectors and developmental regulators for the infant and the mother

International Journal of Environmental Research and Public Health

Volumn 12, Issue 11, 2015, Pages 13981-14020

  Alsaweed, Mohammed ^a,b   Hartmann, Peter E ^a   Geddes, Donna T ^a   Kakulas, Foteini ^a  

^a UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

^b MAJMAAH UNIVERSITY   (Saudi Arabia)

Author keywords

Breastfeeding; Breastmilk; Cells; Development; Human milk; Immune system; Infant formula; Lipids; MicroRNA; RNA; Skim milk

Indexed keywords

BODY FLUID; BREASTFEEDING; GENE EXPRESSION; IMMUNE SYSTEM; INFANT FEEDING; LACTATION; LIPID; MILK; RNA;

ANIMALIA;

IMMUNOLOGIC FACTOR; MICRORNA; PROTECTIVE AGENT;

ADULT; BREAST MILK; CHEMISTRY; FEMALE; GENETICS; HUMAN; IMMUNOLOGY; INFANT; ISOLATION AND PURIFICATION; LACTATION; MIDDLE AGED; NEWBORN; YOUNG ADULT;

ADULT; FEMALE; HUMANS; IMMUNOLOGIC FACTORS; INFANT; INFANT, NEWBORN; LACTATION; MICRORNAS; MIDDLE AGED; MILK, HUMAN; PROTECTIVE AGENTS; YOUNG ADULT;

EID: 84946047152     PISSN: 16617827     EISSN: 16604601     Source Type: Journal    
DOI: 10.3390/ijerph121113981     Document Type: Article

References (221)

1. Lee, R.C.; Feinbaum, R.L.; Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993, 75, 843–854.
2. Bartel, D.P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004, 116, 281–297.
3. He, L.; Hannon, G.J. MicroRNAs: Small RNAs with a big role in gene regulation. Nat. Rev. Genet. 2004, 5, 522–531.
4. Pritchard, C.C.; Cheng, H.H.; Tewari, M. MicroRNA profiling: Approaches and considerations. Nat. Rev. Genet. 2012, 13, 358–369.
5. Fabian, M.R.; Sonenberg, N.; Filipowicz, W. Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem. 2010, 79, 351–379.
6. Krol, J.; Loedige, I.; Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. Genet. 2010, 11, 597–610.
7. Winter, J.; Jung, S.; Keller, S.; Gregory, R.I.; Diederichs, S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat. Cell Biol. 2009, 11, 228–234.
8. Kim, V.N.; Han, J.; Siomi, M.C. Biogenesis of small RNAs in animals. Nat. Rev. Mol. Cell Biol. 2009, 10, 126–139.
9. Du, T.; Zamore, P.D. microPrimer: The biogenesis and function of microRNA. Development 2005, 132, 4645–4652.
10. International Human Genome Sequencing, C. Finishing the euchromatic sequence of the human genome. Nature 2004, 431, 931–945.
11. Williams, A.E. Functional aspects of animal microRNAs. Cell. Mol. Life Sci. 2008, 65, 545–562.
12. O’Driscoll, L. The emerging world of microRNAs. Anticancer Res. 2006, 26, 4271–4278.
13. Houbaviy, H.B.; Murray, M.F.; Sharp, P.A. Embryonic stem cell-specific MicroRNAs. Dev. Cell 2003, 5, 351–358.
14. Judson, R.L.; Babiarz, J.E.; Venere, M.; Blelloch, R. Embryonic stem cell-specific microRNAs promote induced pluripotency. Nat. Biotechnol. 2009, 27, 459–461.
15. Xu, N.; Papagiannakopoulos, T.; Pan, G.; Thomson, J.A.; Kosik, K.S. MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell 2009, 137, 647–658.
16. Huangfu, D.; Maehr, R.; Guo, W.; Eijkelenboom, A.; Snitow, M.; Chen, A.E.; Melton, D.A. Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds. Nat. Biotechnol. 2008, 26, 795–797.
17. Yoshida, Y.; Takahashi, K.; Okita, K.; Ichisaka, T.; Yamanaka, S. Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell 2009, 5, 237–241.
18. Ventura, A.; Young, A.G.; Winslow, M.M.; Lintault, L.; Meissner, A.; Erkeland, S.J.; Newman, J.; Bronson, R.T.; Crowley, D.; Stone, J.R. et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell 2008, 132, 875–886.
19. Xiao, C.; Srinivasan, L.; Calado, D.P.; Patterson, H.C.; Zhang, B.; Wang, J.; Henderson, J.M.; Kutok, J.L.; Rajewsky, K. Lymphoproliferative disease and autoimmunity in mice with increased miR-17–92 expression in lymphocytes. Nat. Immunol. 2008, 9, 405–414.
20. Jing, Q.; Huang, S.; Guth, S.; Zarubin, T.; Motoyama, A.; Chen, J.; Di Padova, F.; Lin, S.C.; Gram, H.; Han, J. Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell 2005, 120, 623–634.
21. Landgraf, P.; Rusu, M.; Sheridan, R.; Sewer, A.; Iovino, N.; Aravin, A.; Pfeffer, S.; Rice, A.; Kamphorst, A.O.; Landthaler, M. et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 2007, 129, 1401–1414.
22. O’Connell, R.M.; Taganov, K.D.; Boldin, M.P.; Cheng, G.; Baltimore, D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc. Natl. Acad. Sci. USA 2007, 104, 1604–1609.
23. Monticelli, S.; Ansel, K.M.; Xiao, C.; Socci, N.D.; Krichevsky, A.M.; Thai, T.H.; Rajewsky, N.; Marks, D.S.; Sander, C.; Rajewsky, K. et al. MicroRNA profiling of the murine hematopoietic system. Genome Biol. 2005, doi:10.1186/gb-2005-6-8-r71.
24. Yang, B.; Lin, H.; Xiao, J.; Lu, Y.; Luo, X.; Li, B.; Zhang, Y.; Xu, C.; Bai, Y.; Wang, H. et al. The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat. Med. 2007, 13, 486–491.
25. Poy, M.N.; Eliasson, L.; Krutzfeldt, J.; Kuwajima, S.; Ma, X.; Macdonald, P.E.; Pfeffer, S.; Tuschl, T.; Rajewsky, N.; Rorsman, P. et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 2004, 432, 226–230.
26. Giraldez, A.J.; Cinalli, R.M.; Glasner, M.E.; Enright, A.J.; Thomson, J.M.; Baskerville, S.; Hammond, S.M.; Bartel, D.P.; Schier, A.F. MicroRNAs regulate brain morphogenesis in zebrafish. Science 2005, 308, 833–838.
27. Mahn, R.; Heukamp, L.C.; Rogenhofer, S.; von Ruecker, A.; Muller, S.C.; Ellinger, J. Circulating microRNAs (miRNA) in serum of patients with prostate cancer. Urology 2011, doi:10.1016/j.urology.2011.01.020.
28. Gotte, M. MicroRNAs in breast cancer pathogenesis. Minerva Ginecol. 2010, 62, 559–571.
29. Si, M.L.; Zhu, S.; Wu, H.; Lu, Z.; Wu, F.; Mo, Y.Y. miR-21-mediated tumor growth. Oncogene 2007, 26, 2799–2803.
30. Weber, J.A.; Baxter, D.H.; Zhang, S.; Huang, D.Y.; Huang, K.H.; Lee, M.J.; Galas, D.J.; Wang, K. The microRNA spectrum in 12 body fluids. Clin. Chem. 2010, 56, 1733–1741.
31. Silveri, L.; Tilly, G.; Vilotte, J.L.; Le Provost, F. MicroRNA involvement in mammary gland development and breast cancer. Reprod. Nutr. Dev. 2006, 46, 549–556.
32. Zhang, L.; Hou, D.; Chen, X.; Li, D.; Zhu, L.; Zhang, Y.; Li, J.; Bian, Z.; Liang, X.; Cai, X. et al. Exogenous plant MIR168a specifically targets mammalian LDLRAP1: Evidence of cross-kingdom regulation by microRNA. Cell Res. 2012, 22, 107–126.
33. Palmer, J.D.; Soule, B.P.; Simone, B.A.; Zaorsky, N.G.; Jin, L.; Simone, N.L. Dietary alterations caused by microRNA: Can food be medicinal? Ageing Res. Rev. 2014, doi:10.1016/j.arr.2014.04.005.
34. Jiang, M.; Sang, X.; Hong, Z. Beyond nutrients: Food-derived microRNAs provide cross-kingdom regulation. Bioessays 2012, 34, 280–284.
35. Alsaweed, M.; Tat-Lai, C.; Newnham, J.; Hartmann, P.E.; Geddes, D.T.; Kakulas, F. Small RNA Sequencing of Human Milk Cells reveals Numerous Known and Novel miRNAs that may be affected by Milk Removal. In Proceedings of the Combined Biological Sciences Meeting, Perth, Australia, 28 August 2015.
36. Zhou, Q.; Li, M.; Wang, X.; Li, Q.; Wang, T.; Zhu, Q.; Zhou, X.; Wang, X.; Gao, X.; Li, X. Immune-related microRNAs are abundant in breast milk exosomes. Int. J. Biol. Sci. 2012, 8, 118–123.
37. Baier, S.R.; Nguyen, C.; Xie, F.; Wood, J.R.; Zempleni, J. MicroRNAs are absorbed in biologically meaningful amounts from nutritionally relevant doses of cow milk and affect gene expression in peripheral blood mononuclear cells, HEK-293 kidney cell cultures, and mouse livers. J. Nutr. 2014, 144, 1495–1500.
38. Wolf, T.; Baier, S.R.; Zempleni, J. The intestinal transport of bovine milk exosomes is mediated by endocytosis in human colon carcinoma Caco-2 cells and rat small intestinal IEC-6 cells. J. Nutr. 2015, doi:10.3945/jn.115.218586.
39. Pieters, B.C.; Arntz, O.J.; Bennink, M.B.; Broeren, M.G.; van Caam, A.P.; Koenders, M.I.; van Lent, P.L.; van den Berg, W.B.; de Vries, M.; van der Kraan, P.M. et al. Commercial cow milk contains physically stable extracellular vesicles expressing immunoregulatory TGF-beta. PLoS ONE 2015, doi:10.1371/journal.pone.0121123.
40. Kramer, M.S. “Breast is best”: The evidence. Early Hum. Dev. 2010, 86, 729–732.
41. Kramer, M.S.; Kakuma, R. The optimal duration of exclusive breastfeeding. J. Adv. Nurs. 2001, 35, 313–315.
42. Wang, K.; Zhang, S.; Weber, J.; Baxter, D.; Galas, D.J. Export of microRNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res. 2010, 38, 7248–7259.
43. Kosaka, N.; Iguchi, H.; Ochiya, T. Circulating microRNA in body fluid: A new potential biomarker for cancer diagnosis and prognosis. Cancer Sci. 2010, 101, 2087–2092.
44. Munch, E.M.; Harris, R.A.; Mohammad, M.; Benham, A.L.; Pejerrey, S.M.; Showalter, L.; Hu, M.; Shope, C.D.; Maningat, P.D.; Gunaratne, P.H. et al. Transcriptome profiling of microRNA by Next-Gen deep sequencing reveals known and novel miRNA species in the lipid fraction of human breast milk. PLoS ONE 2013, doi:10.1371/journal.pone.0050564.
45. Alsaweed, M.; Tat-Lai, C.; Newnham, J.; Hartmann, P.E.; Geddes, D.T.; Kakulas, F. Breastmilk miRNA Primarily Originate from the Mammary Gland. In Proceedings of Combined Biological Sciences Meeting, Perth, Australia, 28 August 2015.
46. Alsaweed, M.; Tat-Lai, C.; Hartmann, P.E.; Geddes, D.T.; Kakulas, F. Human milk miRNAs primarily originate from the mammary gland resulting in unique miRNA profiles of fractionated milk. Scientific Reports 2015, under review.
47. Alsaweed, M.; Hepworth, A.R.; Lefevre, C.; Hartmann, P.E.; Geddes, D.T.; Hassiotou, F. Human milk microRNA and total RNA differ depending on milk fractionation. J. Cell Biochem. 2015, doi:10.1002/jcb.25207.
48. Kosaka, N.; Izumi, H.; Sekine, K.; Ochiya, T. microRNA as a new immune-regulatory agent in breast milk. Silence 2010, doi:10.1186/1758-907X-1-7.
49. Li, Z.; Liu, H.; Jin, X.; Lo, L.; Liu, J. Expression profiles of microRNAs from lactating and non-lactating bovine mammary glands and identification of miRNA related to lactation. BMC Genomics 2012, doi:10.1186/1471-2164-13-731.
50. Avril-Sassen, S.; Goldstein, L.D.; Stingl, J.; Blenkiron, C.; Le Quesne, J.; Spiteri, I.; Karagavriilidou, K.; Watson, C.J.; Tavare, S.; Miska, E.A. et al. Characterisation of microRNA expression in post-natal mouse mammary gland development. BMC Genomics 2009, doi:10.1186/1471-2164-10-548.
51. Gu, Y.; Li, M.; Wang, T.; Liang, Y.; Zhong, Z.; Wang, X.; Zhou, Q.; Chen, L.; Lang, Q.; He, Z. et al. Lactation-related microRNA expression profiles of porcine breast milk exosomes. PLoS ONE 2012, doi:10.1371/journal.pone.0043691.
52. Chen, X.; Gao, C.; Li, H.; Huang, L.; Sun, Q.; Dong, Y.; Tian, C.; Gao, S.; Dong, H.; Guan, D. et al. Identification and characterization of microRNAs in raw milk during different periods of lactation, commercial fluid, and powdered milk products. Cell Res. 2010, 20, 1128–1137.
53. Hata, T.; Murakami, K.; Nakatani, H.; Yamamoto, Y.; Matsuda, T.; Aoki, N. Isolation of bovine milk-derived microvesicles carrying mRNAs and microRNAs. Biochem. Biophys. Res. Commun. 2010, 396, 528–533.
54. Izumi, H.; Kosaka, N.; Shimizu, T.; Sekine, K.; Ochiya, T.; Takase, M. Bovine milk contains microRNA and messenger RNA that are stable under degradative conditions. J. Dairy Sci. 2012, 95, 4831–4841.
55. Chen, T.; Xi, Q.Y.; Ye, R.S.; Cheng, X.; Qi, Q.E.; Wang, S.B.; Shu, G.; Wang, L.N.; Zhu, X.T.; Jiang, Q.Y. et al. Exploration of microRNAs in porcine milk exosomes. BMC Genomics 2014, 15, doi:10.1186/1471-2164-15-100.
56. Izumi, H.; Kosaka, N.; Shimizu, T.; Sekine, K.; Ochiya, T.; Takase, M. Time-dependent expression profiles of microRNAs and mRNAs in rat milk whey. PLoS ONE 2014, doi:10.1371/journal.pone.0088843.
57. Modepalli, V.; Kumar, A.; Hinds, L.A.; Sharp, J.A.; Nicholas, K.R.; Lefevre, C. Differential temporal expression of milk miRNA during the lactation cycle of the marsupial tammar wallaby (Macropus eugenii). BMC Genomics 2014, doi:10.1186/1471-2164-15-1012.
58. Hassiotou, F.; Geddes, D.T.; Hartmann, P.E. Cells in human milk: State of the science. J. Hum. Lact. 2013, 29, 171–182.
59. Molinari, C.E.; Casadio, Y.S.; Hartmann, B.T.; Arthur, P.G.; Hartmann, P.E. Longitudinal analysis of protein glycosylation and beta-casein phosphorylation in term and preterm human milk during the first 2 months of lactation. Br. J. Nutr. 2013, 110, 105–115.
60. Mitoulas, L.R.; Kent, J.C.; Cox, D.B.; Owens, R.A.; Sherriff, J.L.; Hartmann, P.E. Variation in fat, lactose and protein in human milk over 24 h and throughout the first year of lactation. Br. J. Nutr. 2002, 88, 29–37.
61. Hassiotou, F.; Hepworth, A.R.; Williams, T.M.; Twigger, A.J.; Perrella, S.; Lai, C.T.; Filgueira, L.; Geddes, D.T.; Hartmann, P.E. Breastmilk cell and fat contents respond similarly to removal of breastmilk by the infant. PLoS ONE 2013, doi:10.1371/journal.pone.0078232.
62. Hassiotou, F.; Hepworth, A.R.; Metzger, P.; Tat Lai, C.; Trengove, N.; Hartmann, P.E.; Filgueira, L. Maternal and infant infections stimulate a rapid leukocyte response in breastmilk. Clin. Transl. Immunol. 2013, doi:10.1038/cti.2013.1.
63. Powe, C.E.; Knott, C.D.; Conklin-Brittain, N. Infant sex predicts breast milk energy content. Am. J. Hum. Biol. 2010, 22, 50–54.
64. Bachour, P.; Yafawi, R.; Jaber, F.; Choueiri, E.; Abdel-Razzak, Z. Effects of smoking, mother’s age, body mass index, and parity number on lipid, protein, and secretory immunoglobulin a concentrations of human milk. Breastfeed. Med. 2012, 7, 179–188.
65. Bauer, J.; Gerss, J. Longitudinal analysis of macronutrients and minerals in human milk produced by mothers of preterm infants. Clin. Nutr. 2011, 30, 215–220.
66. Zhang, M.W.; Jin, M.J.; Yu, Y.X.; Zhang, S.C.; Liu, B.; Jiang, X.; Pan, Y.F.; Li, Q.I.; Ma, S.Y.; Chen, K. Associations of lifestyle-related factors, hsa-miR-149 and hsa-miR-605 gene polymorphisms with gastrointestinal cancer risk. Mol. Carcinog. 2012, doi:10.1002/mc.20863.
67. Makrides, M.; Neumann, M.A.; Gibson, R.A. Effect of maternal docosahexaenoic acid (DHA) supplementation on breast milk composition. Eur. J. Clin. Nutr. 1996, 50, 352–357.
68. Melnik, B.C.; John, S.M.; Schmitz, G. Milk consumption during pregnancy increases birth weight, a risk factor for the development of diseases of civilization. J. Transl. Med. 2015, doi:10.1186/s12967- 014-0377-9.
69. Jiang, H.; Wu, W.; Zhang, M.; Li, J.; Peng, Y.; Miao, T.T.; Zhu, H.; Xu, G. Aberrant upregulation of miR-21 in placental tissues of macrosomia. J. Perinatol. 2014, 34, 658–663.
70. Hassiotou, F.; Geddes, D.T. Immune cell-mediated protection of the mammary gland and the infant during breastfeeding. Adv. Nutr. 2015, 6, 267–275.
71. Lawless, N.; Reinhardt, T.A.; Bryan, K.; Baker, M.; Pesch, B.; Zimmerman, D.; Zuelke, K.; Sonstegard, T.; O’Farrelly, C.; Lippolis, J.D. et al. MicroRNA regulation of bovine monocyte inflammatory and metabolic networks in an in vivo infection model. G3 (Bethesda) 2014, 4, 957–971.
72. Sourvinou, I.S.; Markou, A.; Lianidou, E.S. Quantification of circulating miRNAs in plasma: Effect of preanalytical and analytical parameters on their isolation and stability. J. Mol. Diagn. 2013, 15, 827–834.
73. Wang, M.; Moisa, S.; Khan, M.J.; Wang, J.; Bu, D.; Loor, J.J. MicroRNA expression patterns in the bovine mammary gland are affected by stage of lactation. J. Dairy Sci. 2012, 95, 6529–6535.
74. Bian, Y.; Lei, Y.; Wang, C.; Wang, J.; Wang, L.; Liu, L.; Liu, L.; Gao, X.; Li, Q. Epigenetic regulation of miR-29s affects the lactation activity of dairy cow mammary epithelial cells. J. Cell. Physiol. 2015, 230, 2152–2163.
75. Dickinson, B.; Zhang, Y.; Petrick, J.S.; Heck, G.; Ivashuta, S.; Marshall, W.S. Lack of detectable oral bioavailability of plant microRNAs after feeding in mice. Nat. Biotechnol. 2013, 31, 965–967.
76. Mu, J.; Zhuang, X.; Wang, Q.; Jiang, H.; Deng, Z.B.; Wang, B.; Zhang, L.; Kakar, S.; Jun, Y.; Miller, D. et al. Interspecies communication between plant and mouse gut host cells through edible plant derived exosome-like nanoparticles. Mol. Nutr. Food Res. 2014, 58, 1561–1573.
77. Garcia-Segura, L.; Perez-Andrade, M.; Miranda-Rios, J. The emerging role of MicroRNAs in the regulation of gene expression by nutrients. J. Nutrigenet. Nutrigenomics 2013, 6, 16–31.
78. Tian, T.; Wang, Y.; Wang, H.; Zhu, Z.; Xiao, Z. Visualizing of the cellular uptake and intracellular trafficking of exosomes by live-cell microscopy. J. Cell Biochem. 2010, 111, 488–496.
79. Tian, T.; Zhu, Y.L.; Hu, F.H.; Wang, Y.Y.; Huang, N.P.; Xiao, Z.D. Dynamics of exosome internalization and trafficking. J. Cell. Physiol. 2013, 228, 1487–1495.
80. Tian, T.; Zhu, Y.L.; Zhou, Y.Y.; Liang, G.F.; Wang, Y.Y.; Hu, F.H.; Xiao, Z.D. Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J. Biol. Chem. 2014, 289, 22258–22267.
81. Arntz, O.J.; Pieters, B.C.; Oliveira, M.C.; Broeren, M.G.; Bennink, M.B.; de Vries, M.; van Lent, P.L.; Koenders, M.I.; van den Berg, W.B. et al. Oral administration of bovine milk derived extracellular vesicles attenuates arthritis in two mouse models. Mol. Nutr. Food Res. 2015, 59, 1701–1712.
82. Hassiotou, F.; Mobley, A.; Geddes, D.T.; Hartmann, P.E.; Wilkie, T.M. Breastmilk Imparts the Mother’s Stem Cells to the Infant; Experimental Biology: Boston, MA, USA, 2015.
83. Hassiotou, F.; Mobley, A.; Ocal, O.; Filgueira, L.; Geddes, D.T.; Hartmann, P.E.; Wilkie, T.M. Breastmilk Stem Cell Transfer from the Mother to Neonatal Organs: A Route of Migration and Integration; International Society for Research in Human Milk and Lactation: Charleston, SC, USA, 2014.
84. Sun, Q.; Chen, X.; Yu, J.; Zen, K.; Zhang, C.Y.; Li, L. Immune modulatory function of abundant immune-related microRNAs in microvesicles from bovine colostrum. Protein Cell 2013, 4, 197–210.
85. Ji, L.; Chen, X. Regulation of small RNA stability: Methylation and beyond. Cell Res. 2012, 22, 624–636.
86. Chen, X.; Ba, Y.; Ma, L.; Cai, X.; Yin, Y.; Wang, K.; Guo, J.; Zhang, Y.; Chen, J.; Guo, X. et al. Characterization of microRNAs in serum: A novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008, 18, 997–1006.
87. Bai, W.L.; Yin, R.H.; Yang, R.J.; Khan, W.A.; Ma, Z.J.; Zhao, S.J.; Jiang, W.Q.; Wang, Z.Y.; Zhu, Y.B.; Luo, G.B. et al. Technical note: Identification of suitable normalizers for microRNA expression analysis in milk somatic cells of the yak (Bos grunniens). J. Dairy Sci. 2013, 96, 4529–4534.
88. Mitchell, P.S.; Parkin, R.K.; Kroh, E.M.; Fritz, B.R.; Wyman, S.K.; Pogosova-Agadjanyan, E.L.; Peterson, A.; Noteboom, J.; O’Briant, K.C.; Allen, A. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl. Acad. Sci. USA 2008, 105, 10513–10518.
89. Gilad, S.; Meiri, E.; Yogev, Y.; Benjamin, S.; Lebanony, D.; Yerushalmi, N.; Benjamin, H.; Kushnir, M.; Cholakh, H.; Melamed, N. et al. Serum microRNAs are promising novel biomarkers. PLoS ONE 2008, doi:10.1371/journal.pone.0003148.
90. Fallingborg, J. Intraluminal pH of the human gastrointestinal tract. Dan. Med. Bull. 1999, 46, 183–196.
91. Title, A.C.; Denzler, R.; Stoffel, M. Uptake and function studies of maternal milk-derived microRNAs. J. Biol. Chem. 2015, doi:10.1074/jbc.M115.676734.
92. Bar-Sagi, D.; Fernandez, A.; Feramisco, J.R. Regulation of membrane turnover by ras proteins. Biosci. Rep. 1987, 7, 427–434.
93. Salunkhe, V.A.; Esguerra, J.L.; Ofori, J.K.; Mollet, I.G.; Braun, M.; Stoffel, M.; Wendt, A.; Eliasson, L. Modulation of microRNA-375 expression alters voltage-gated Na(+) channel properties and exocytosis in insulin-secreting cells. Acta Physiol. (Oxf.) 2015, 213, 882–892.
94. Yang, J.; Farmer, L.M.; Agyekum, A.A.; Hirschi, K.D. Detection of dietary plant-based small RNAs in animals. Cell Res. 2015, 25, 517–520.
95. Pothof, J.; Verkaik, N.S.; van, I.W.; Wiemer, E.A.; Ta, V.T.; van der Horst, G.T.; Jaspers, N.G.; van Gent, D.C.; Hoeijmakers, J.H.; Persengiev, S.P. MicroRNA-mediated gene silencing modulates the UV-induced DNA-damage response. EMBO J. 2009, 28, 2090–2099.
96. Kagias, K.; Podolska, A.; Pocock, R. Reliable reference miRNAs for quantitative gene expression analysis of stress responses in Caenorhabditis elegans. BMC Genomics 2014, doi:10.1186/1471- 2164-15-222.
97. Kraemer, A.; Chen, I.P.; Henning, S.; Faust, A.; Volkmer, B.; Atkinson, M.J.; Moertl, S.; Greinert, R. UVA and UVB irradiation differentially regulate microRNA expression in human primary keratinocytes. PLoS ONE 2013, doi:10.1371/journal.pone.0083392.
98. Syed, D.N.; Khan, M.I.; Shabbir, M.; Mukhtar, H. MicroRNAs in skin response to UV radiation. Curr. Drug Targets 2013, 14, 1128–1134.
99. Grignol, V.; Fairchild, E.T.; Zimmerer, J.M.; Lesinski, G.B.; Walker, M.J.; Magro, C.M.; Kacher, J.E.; Karpa, V.I.; Clark, J.; Nuovo, G. et al. MiR-21 and miR-155 are associated with mitotic activity and lesion depth of borderline melanocytic lesions. Br. J. Cancer 2011, 105, 1023–1029.
100. Lindsay, M.A. microRNAs and the immune response. Trends Immunol 2008, 29, 343–351.
101. Lu, L.F.; Liston, A. MicroRNA in the immune system, microRNA as an immune system. Immunology 2009, 127, 291–298.
102. Pauley, K.M.; Cha, S.; Chan, E.K. MicroRNA in autoimmunity and autoimmune diseases. J. Autoimmun. 2009, 32, 189–194.
103. Lu, T.X.; Munitz, A.; Rothenberg, M.E. MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression. J. Immunol. 2009, 182, 4994–5002.
104. Oddy, W.H. The long-term effects of breastfeeding on asthma and atopic disease. Adv. Exp. Med. Biol. 2009, 639, 237–2351.
105. Chen, C.Z.; Li, L.; Lodish, H.F.; Bartel, D.P. MicroRNAs modulate hematopoietic lineage differentiation. Science 2004, 303, 83–86.
106. Vigorito, E.; Perks, K.L.; Abreu-Goodger, C.; Bunting, S.; Xiang, Z.; Kohlhaas, S.; Das, P.P.; Miska, E.A.; Rodriguez, A.; Bradley, A. et al. microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 2007, 27, 847–859.
107. Li, Q.J.; Chau, J.; Ebert, P.J.; Sylvester, G.; Min, H.; Liu, G.; Braich, R.; Manoharan, M.; Soutschek, J.; Skare, P. et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 2007, 129, 147–161.
108. De Yebenes, V.G.; Belver, L.; Pisano, D.G.; Gonzalez, S.; Villasante, A.; Croce, C.; He, L.; Ramiro, A.R. miR-181b negatively regulates activation-induced cytidine deaminase in B cells. J. Exp. Med. 2008, 205, 2199–2206.
109. Iliopoulos, D.; Jaeger, S.A.; Hirsch, H.A.; Bulyk, M.L.; Struhl, K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol. Cell 2010, 39, 493–506.
110. Quinn, S.R.; Mangan, N.E.; Caffrey, B.E.; Gantier, M.P.; Williams, B.R.; Hertzog, P.J.; McCoy, C.E.; O’Neill, L.A. The role of Ets2 transcription factor in the induction of microRNA-155 (miR-155) by lipopolysaccharide and its targeting by interleukin-10. J. Biol. Chem. 2014, 289, 4316–4325.
111. Tili, E.; Michaille, J.J.; Cimino, A.; Costinean, S.; Dumitru, C.D.; Adair, B.; Fabbri, M.; Alder, H.; Liu, C.G.; Calin, G.A. et al. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J. Immunol. 2007, 179, 5082–5089.
112. Fontana, L.; Pelosi, E.; Greco, P.; Racanicchi, S.; Testa, U.; Liuzzi, F.; Croce, C.M.; Brunetti, E.; Grignani, F.; Peschle, C. MicroRNAs 17-5p-20a-106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation. Nat. Cell Biol. 2007, 9, 775–787.
113. Admyre, C.; Johansson, S.M.; Qazi, K.R.; Filen, J.J.; Lahesmaa, R.; Norman, M.; Neve, E.P.; Scheynius, A.; Gabrielsson, S. Exosomes with immune modulatory features are present in human breast milk. J. Immunol. 2007, 179, 1969–1978.
114. Tanaka, M.; Oikawa, K.; Takanashi, M.; Kudo, M.; Ohyashiki, J.; Ohyashiki, K.; Kuroda, M. Down-regulation of miR-92 in human plasma is a novel marker for acute leukemia patients. PLoS ONE 2009, doi:10.1371/journal.pone.0005532.
115. Ohyashiki, K.; Umezu, T.; Yoshizawa, S.; Ito, Y.; Ohyashiki, M.; Kawashima, H.; Tanaka, M.; Kuroda, M.; Ohyashiki, J.H. Clinical impact of down-regulated plasma miR-92a levels in non-Hodgkin’s lymphoma. PLoS ONE 2011, doi:10.1371/journal.pone.0016408.
116. Taganov, K.D.; Boldin, M.P.; Chang, K.J.; Baltimore, D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl. Acad. Sci. USA 2006, 103, 12481–12486.
117. Perry, M.M.; Moschos, S.A.; Williams, A.E.; Shepherd, N.J.; Larner-Svensson, H.M.; Lindsay, M.A. Rapid changes in microRNA-146a expression negatively regulate the IL-1beta-induced inflammatory response in human lung alveolar epithelial cells. J. Immunol. 2008, 180, 5689–5698.
118. Fukao, T.; Fukuda, Y.; Kiga, K.; Sharif, J.; Hino, K.; Enomoto, Y.; Kawamura, A.; Nakamura, K.; Takeuchi, T.; Tanabe, M. An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling. Cell 2007, 129, 617–631.
119. Johnnidis, J.B.; Harris, M.H.; Wheeler, R.T.; Stehling-Sun, S.; Lam, M.H.; Kirak, O.; Brummelkamp, T.R.; Fleming, M.D.; Camargo, F.D. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature 2008, 451, 1125–1129.
120. Fazi, F.; Rosa, A.; Fatica, A.; Gelmetti, V.; de Marchis, M.L.; Nervi, C.; Bozzoni, I. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Cell 2005, 123, 819–831.
121. Zhou, B.; Wang, S.; Mayr, C.; Bartel, D.P.; Lodish, H.F. miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely. Proc. Natl. Acad. Sci. USA 2007, 104, 7080–7085.
122. Xiao, C.; Calado, D.P.; Galler, G.; Thai, T.H.; Patterson, H.C.; Wang, J.; Rajewsky, N.; Bender, T.P.; Rajewsky, K. MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 2007, 131, 146–159.
123. Gaziel-Sovran, A.; Segura, M.F.; Di Micco, R.; Collins, M.K.; Hanniford, D.; Vega-Saenz de Miera, E.; Rakus, J.F.; Dankert, J.F.; Shang, S.; Kerbel, R.S. et al. miR-30b/30d regulation of GalNAc transferases enhances invasion and immunosuppression during metastasis. Cancer Cell 2011, 20, 104–118.
124. Stittrich, A.B.; Haftmann, C.; Sgouroudis, E.; Kuhl, A.A.; Hegazy, A.N.; Panse, I.; Riedel, R.; Flossdorf, M.; Dong, J.; Fuhrmann, F. et al. The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat. Immunol. 2010, 11, 1057–1062.
125. Navarro, A.; Gaya, A.; Martinez, A.; Urbano-Ispizua, A.; Pons, A.; Balague, O.; Gel, B.; Abrisqueta, P.; Lopez-Guillermo, A.; Artells, R. et al. MicroRNA expression profiling in classic Hodgkin lymphoma. Blood 2008, 111, 2825–2832.
126. Ma, F.; Xu, S.; Liu, X.; Zhang, Q.; Xu, X.; Liu, M.; Hua, M.; Li, N.; Yao, H.; Cao, X. The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-gamma. Nat. Immunol. 2011, 12, 861–869.
127. Pekarsky, Y.; Santanam, U.; Cimmino, A.; Palamarchuk, A.; Efanov, A.; Maximov, V.; Volinia, S.; Alder, H.; Liu, C.G.; Rassenti, L. et al. Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181. Cancer Res. 2006, 66, 11590–11593.
128. Fulci, V.; Chiaretti, S.; Goldoni, M.; Azzalin, G.; Carucci, N.; Tavolaro, S.; Castellano, L.; Magrelli, A.; Citarella, F.; Messina, M. et al. Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia. Blood 2007, 109, 4944–4951.
129. Calin, G.A.; Dumitru, C.D.; Shimizu, M.; Bichi, R.; Zupo, S.; Noch, E.; Aldler, H.; Rattan, S.; Keating, M.; Rai, K. et al. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. USA 2002, 99, 15524–15529.
130. Pauley, K.M.; Satoh, M.; Chan, A.L.; Bubb, M.R.; Reeves, W.H.; Chan, E.K. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res. Ther. 2008, doi:10.1186/ar2493.
131. Lawrie, C.H.; Soneji, S.; Marafioti, T.; Cooper, C.D.; Palazzo, S.; Paterson, J.C.; Cattan, H.; Enver, T.; Mager, R.; Boultwood, J. et al. MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma. Int. J. Cancer 2007, 121, 1156–1161.
132. Koralov, S.B.; Muljo, S.A.; Galler, G.R.; Krek, A.; Chakraborty, T.; Kanellopoulou, C.; Jensen, K.; Cobb, B.S.; Merkenschlager, M.; Rajewsky, N. et al. Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell 2008, 132, 860–874.
133. Mendell, J.T. miRiad roles for the miR-17–92 cluster in development and disease. Cell 2008, 133, 217–222.
134. Hassiotou, F.; Beltran, A.; Chetwynd, E.; Stuebe, A.M.; Twigger, A.J.; Metzger, P.; Trengove, N.; Lai, C.T.; Filgueira, L.; Blancafort, P. et al. Breastmilk is a novel source of stem cells with multilineage differentiation potential. Stem Cells 2012, 30, 2164–2174.
135. Hassiotou, F.; Hepworth, A.R.; Beltran, A.S.; Mathews, M.M.; Stuebe, A.M.; Hartmann, P.E.; Filgueira, L.; Blancafort, P. Expression of the pluripotency transcription Factor OCT4 in the normal and aberrant mammary gland. Front. Oncol. 2013, doi:10.3389/fonc.2013.00079.
136. Sonkoly, E.; Stahle, M.; Pivarcsi, A. MicroRNAs and immunity: Novel players in the regulation of normal immune function and inflammation. Semin. Cancer Biol. 2008, 18, 131–140.
137. Keller, M.A.; Gendreau-Reid, L.; Heiner, D.C.; Rodriguez, A.; Short, J.A. IgG4 in human colostrum and human milk: Continued local production or selective transport from serum. Acta Paediatr. Scand. 1988, 77, 24–29.
138. Peitersen, B.; Bohn, L.; Andersen, H. Quantitative determination of immunoglobulins, lysozyme, and certain electrolytes in breast milk during the entire period of lactation, during a 24-h period, and in milk from the individual mammary gland. Acta Paediatr. Scand. 1975, 64, 709–717.
139. Goldman, A.S.; Garza, C.; Nichols, B.L.; Goldblum, R.M. Immunologic factors in human milk during the first year of lactation. J. Pediatr. 1982, 100, 563–567.
140. Xiao, C.; Rajewsky, K. MicroRNA control in the immune system: Basic principles. Cell 2009, 136, 26–36.
141. Meng, F.; Henson, R.; Wehbe-Janek, H.; Smith, H.; Ueno, Y.; Patel, T. The MicroRNA let-7a modulates interleukin-6-dependent STAT-3 survival signaling in malignant human cholangiocytes. J. Biol. Chem. 2007, 282, 8256–8264.
142. Sheedy, F.J.; Palsson-McDermott, E.; Hennessy, E.J.; Martin, C.; O’Leary, J.J.; Ruan, Q.; Johnson, D.S.; Chen, Y.; O’Neill, L.A. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat. Immunol. 2010, 11, 141–147.
143. Manetti, R.; Parronchi, P.; Giudizi, M.G.; Piccinni, M.P.; Maggi, E.; Trinchieri, G.; Romagnani, S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J. Exp. Med. 1993, 177, 1199–1204.
144. Jennewein, C.; von Knethen, A.; Schmid, T.; Brune, B. MicroRNA-27b contributes to lipopolysaccharide-mediated peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA destabilization. J. Biol. Chem. 2010, 285, 11846–11853.
145. Gu, Z.; Eleswarapu, S.; Jiang, H. Identification and characterization of microRNAs from the bovine adipose tissue and mammary gland. FEBS Lett. 2007, 581, 981–988.
146. Yu, D.; Tan, A.H.; Hu, X.; Athanasopoulos, V.; Simpson, N.; Silva, D.G.; Hutloff, A.; Giles, K.M.; Leedman, P.J.; Lam, K.P. et al. Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 2007, 450, 299–303.
147. Cobb, B.S.; Hertweck, A.; Smith, J.; O’Connor, E.; Graf, D.; Cook, T.; Smale, S.T.; Sakaguchi, S.; Livesey, F.J.; Fisher, A.G.; Merkenschlager, M. A role for Dicer in immune regulation. J. Exp. Med. 2006, 203, 2519–2527.
148. Thai, T.H.; Calado, D.P.; Casola, S.; Ansel, K.M.; Xiao, C.; Xue, Y.; Murphy, A.; Frendewey, D.; Valenzuela, D.; Kutok, J.L. et al. Regulation of the germinal center response by microRNA-155. Science 2007, 316, 604–608.
149. Kuhn, A.R.; Schlauch, K.; Lao, R.; Halayko, A.J.; Gerthoffer, W.T.; Singer, C.A. MicroRNA expression in human airway smooth muscle cells: Role of miR-25 in regulation of airway smooth muscle phenotype. Am. J. Respir. Cell Mol. Biol. 2010, 42, 506–513.
150. Lei, B.X.; Liu, Z.H.; Li, Z.J.; Li, C.; Deng, Y.F. miR-21 induces cell proliferation and suppresses the chemosensitivity in glioblastoma cells via downregulation of FOXO1. Int. J. Clin. Exp. Med. 2014, 7, 2060–2066.
151. Song, W.; Wang, L.; Wang, L.; Li, Q. Interplay of miR-21 and FoxO1 modulates growth of pancreatic ductal adenocarcinoma. Tumour Biol. 2015, 36, 4741–4745.
152. Gregory, P.A.; Bert, A.G.; Paterson, E.L.; Barry, S.C.; Tsykin, A.; Farshid, G.; Vadas, M.A.; Khew-Goodall, Y.; Goodall, G.J. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat. Cell Biol. 2008, 10, 593–601.
153. Brabletz, T.; Jung, A.; Hlubek, F.; Lohberg, C.; Meiler, J.; Suchy, U.; Kirchner, T. Negative regulation of CD4 expression in T cells by the transcriptional repressor ZEB. Int. Immunol. 1999, 11, 1701–1708.
154. Naeem, A.; Zhong, K.; Moisa, S.J.; Drackley, J.K.; Moyes, K.M.; Loor, J.J. Bioinformatics analysis of microRNA and putative target genes in bovine mammary tissue infected with Streptococcus uberis. J. Dairy Sci. 2012, 95, 6397–6408.
155. Vickers, K.C.; Remaley, A.T. Lipid-based carriers of microRNAs and intercellular communication. Curr. Opin. Lipidol. 2012, 23, 91–97.
156. Rayner, K.J.; Hennessy, E.J. Extracellular communication via microRNA: Lipid particles have a new message. J. Lipid Res. 2013, 54, 1174–1181.
157. Fernandez-Hernando, C.; Suarez, Y.; Rayner, K.J.; Moore, K.J. MicroRNAs in lipid metabolism. Curr. Opin. Lipidol. 2011, 22, 86–92.
158. Rayner, K.J.; Suarez, Y.; Davalos, A.; Parathath, S.; Fitzgerald, M.L.; Tamehiro, N.; Fisher, E.A.; Moore, K.J.; Fernandez-Hernando, C. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 2010, 328, 1570–1573.
159. Najafi-Shoushtari, S.H.; Kristo, F.; Li, Y.; Shioda, T.; Cohen, D.E.; Gerszten, R.E.; Naar, A.M. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 2010, 328, 1566–1569.
160. Schmitz, G.; Langmann, T. Structure, function and regulation of the ABC1 gene product. Curr. Opin. Lipidol. 2001, 12, 129–140.
161. Yvan-Charvet, L.; Wang, N.; Tall, A.R. Role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 139–143.
162. Chen, T.; Huang, Z.; Wang, L.; Wang, Y.; Wu, F.; Meng, S.; Wang, C. MicroRNA-125a-5p partly regulates the inflammatory response, lipid uptake, and ORP9 expression in oxLDL-stimulated monocyte/macrophages. Cardiovasc. Res. 2009, 83, 131–139.
163. Olkkonen, V.M.; Levine, T.P. Oxysterol binding proteins: In more than one place at one time? Biochem. Cell Biol. 2004, 82, 87–98.
164. Raychaudhuri, S.; Im, Y.J.; Hurley, J.H.; Prinz, W.A. Nonvesicular sterol movement from plasma membrane to ER requires oxysterol-binding protein-related proteins and phosphoinositides. J. Cell Biol. 2006, 173, 107–119.
165. Lin, X.; Luo, J.; Zhang, L.; Wang, W.; Gou, D. MiR-103 controls milk fat accumulation in goat (Capra hircus) mammary gland during lactation. PLoS ONE 2013, doi:10.1371/journal. pone.0079258.
166. Sun, L.; Xie, H.; Mori, M.A.; Alexander, R.; Yuan, B.; Hattangadi, S.M.; Liu, Q.; Kahn, C.R.; Lodish, H.F. Mir193b-365 is essential for brown fat differentiation. Nat. Cell Biol. 2011, 13, 958–965.
167. Thery, C.; Zitvogel, L.; Amigorena, S. Exosomes: Composition, biogenesis and function. Nat. Rev. Immunol. 2002, 2, 569–579.
168. Subra, C.; Laulagnier, K.; Perret, B.; Record, M. Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie 2007, 89, 205–212.
169. Huber, J.; Vales, A.; Mitulovic, G.; Blumer, M.; Schmid, R.; Witztum, J.L.; Binder, B.R.; Leitinger, N. Oxidized membrane vesicles and blebs from apoptotic cells contain biologically active oxidized phospholipids that induce monocyte-endothelial interactions. Arterioscler. Thromb. Vasc. Biol. 2002, 22, 101–107.
170. Zhang, Y.; Liu, D.; Chen, X.; Li, J.; Li, L.; Bian, Z.; Sun, F.; Lu, J.; Yin, Y.; Cai, X. et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol. Cell 2010, 39, 133–144.
171. Kopecki, Z.; Luchetti, M.M.; Adams, D.H.; Strudwick, X.; Mantamadiotis, T.; Stoppacciaro, A.; Gabrielli, A.; Ramsay, R.G.; Cowin, A.J. Collagen loss and impaired wound healing is associated with c-Myb deficiency. J. Pathol. 2007, 211, 351–361.
172. Valadi, H.; Ekstrom, K.; Bossios, A.; Sjostrand, M.; Lee, J.J.; Lotvall, J.O. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 2007, 9, 654–659.
173. Liang, Y.; Ridzon, D.; Wong, L.; Chen, C. Characterization of microRNA expression profiles in normal human tissues. BMC Genomics 2007, doi:10.1186/1471-2164-8-166.
174. Wang, V.; Wu, W. MicroRNA-based therapeutics for cancer. BioDrugs 2009, 23, 15–23.
175. Bader, A.G.; Brown, D.; Winkler, M. The promise of microRNA replacement therapy. Cancer Res. 2010, 70, 7027–7030.
176. Duursma, A.M.; Kedde, M.; Schrier, M.; le Sage, C.; Agami, R. miR-148 targets human DNMT3b protein coding region. RNA 2008, 14, 872–877.
177. Gao, Y.; Schug, J.; McKenna, L.B.; Le Lay, J.; Kaestner, K.H.; Greenbaum, L.E. Tissue-specific regulation of mouse microRNA genes in endoderm-derived tissues. Nucleic Acids Res. 2011, 39, 454–463.
178. Sempere, L.F.; Freemantle, S.; Pitha-Rowe, I.; Moss, E.; Dmitrovsky, E.; Ambros, V. Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol. 2004, doi:10.1186/gb- 2004-5-3-r13.
179. Szafranska, A.E.; Davison, T.S.; John, J.; Cannon, T.; Sipos, B.; Maghnouj, A.; Labourier, E.; Hahn, S.A. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene 2007, 26, 4442–4452.
180. Masaki, S.; Ohtsuka, R.; Abe, Y.; Muta, K.; Umemura, T. Expression patterns of microRNAs 155 and 451 during normal human erythropoiesis. Biochem. Biophys. Res. Commun. 2007, 364, 509–514.
181. Wang, S.; Aurora, A.B.; Johnson, B.A.; Qi, X.; McAnally, J.; Hill, J.A.; Richardson, J.A.; Bassel-Duby, R.; Olson, E.N. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev. Cell 2008, 15, 261–271.
182. Zhu, H.; Fan, G.C. Extracellular/circulating microRNAs and their potential role in cardiovascular disease. Am. J. Cardiovasc. Dis. 2011, 1, 138–149.
183. Wang, K.; Zhang, S.; Marzolf, B.; Troisch, P.; Brightman, A.; Hu, Z.; Hood, L.E.; Galas, D.J. Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proc. Natl. Acad. Sci. USA 2009, 106, 4402–4407.
184. Neville, M.C.; Anderson, S.M.; McManaman, J.L.; Badger, T.M.; Bunik, M.; Contractor, N.; Crume, T.; Dabelea, D.; Donovan, S.M.; Forman, N. et al. Lactation and neonatal nutrition: Defining and refining the critical questions. J. Mammary Gland Biol. Neoplasia 2012, 17, 167–188.
185. Baumgartner, S.; Martin, D.; Hagios, C.; Chiquet-Ehrismann, R. Tenm, a Drosophila gene related to tenascin, is a new pair-rule gene. EMBO J. 1994, 13, 3728–3740.
186. Oohashi, T.; Zhou, X.H.; Feng, K.; Richter, B.; Morgelin, M.; Perez, M.T.; Su, W.D.; Chiquet-Ehrismann, R.; Rauch, U.; Fassler, R. Mouse ten-m/Odz is a new family of dimeric type II transmembrane proteins expressed in many tissues. J. Cell Biol. 1999, 145, 563–577.
187. Zheng, L.; Michelson, Y.; Freger, V.; Avraham, Z.; Venken, K.J.; Bellen, H.J.; Justice, M.J.; Wides, R. Drosophila Ten-m and filamin affect motor neuron growth cone guidance. PLoS ONE 2011, doi:10.1371/journal.pone.0022956.
188. Chen, Y.; Siegel, F.; Kipschull, S.; Haas, B.; Frohlich, H.; Meister, G.; Pfeifer, A. miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit. Nat. Commun. 2013, doi:10.1038/ncomms2742.
189. He, A.; Zhu, L.; Gupta, N.; Chang, Y.; Fang, F. Overexpression of micro ribonucleic acid 29, highly up-regulated in diabetic rats, leads to insulin resistance in 3T3-L1 adipocytes. Mol. Endocrinol. 2007, 21, 2785–2794.
190. Dehwah, M.A.; Xu, A.; Huang, Q. MicroRNAs and type 2 diabetes/obesity. J. Genet. Genomics 2012, 39, 11–18.
191. Hassiotou, F.; Geddes, D.T. Programming of appetite control during breastfeeding as a preventative strategy against the obesity epidemic. J. Hum. Lact. 2014, 30, 136–142.
192. Van Kouwenhove, M.; Kedde, M.; Agami, R. MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nat. Rev. Cancer 2011, 11, 644–656.
193. Calin, G.A.; Croce, C.M. MicroRNA signatures in human cancers. Nat. Rev. Cancer 2006, 6, 857–866.
194. Gaard, M.; Tretli, S.; Loken, E.B. Dietary fat and the risk of breast cancer: A prospective study of 25,892 Norwegian women. Int. J. Cancer 1995, 63, 13–17.
195. Qin, L.Q.; Xu, J.Y.; Tezuka, H.; Li, J.; Arita, J.; Hoshi, K.; Sato, A. Consumption of commercial whole and non-fat milk increases the incidence of 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats. Cancer Detect. Prev. 2007, 31, 339–343.
196. Allen, N.E.; Key, T.J.; Appleby, P.N.; Travis, R.C.; Roddam, A.W.; Tjonneland, A.; Johnsen, N.F.; Overvad, K.; Linseisen, J.; Rohrmann, S. et al. Animal foods, protein, calcium and prostate cancer risk: The European Prospective Investigation into Cancer and Nutrition. Br. J. Cancer 2008, 98, 1574–1581.
197. Song, Y.; Chavarro, J.E.; Cao, Y.; Qiu, W.; Mucci, L.; Sesso, H.D.; Stampfer, M.J.; Giovannucci, E.; Pollak, M.; Liu, S. et al. Whole milk intake is associated with prostate cancer-specific mortality among U.S. male physicians. J. Nutr. 2013, 143, 189–196.
198. Torfadottir, J.E.; Steingrimsdottir, L.; Mucci, L.; Aspelund, T.; Kasperzyk, J.L.; Olafsson, O.; Fall, K.; Tryggvadottir, L.; Harris, T.B.; Launer, L. et al. Milk intake in early life and risk of advanced prostate cancer. Am. J. Epidemiol. 2012, 175, 144–153.
199. Duarte-Salles, T.; Fedirko, V.; Stepien, M.; Trichopoulou, A.; Bamia, C.; Lagiou, P.; Lukanova, A.; Trepo, E.; Overvad, K.; Tjonneland, A. et al. Dairy products and risk of hepatocellular carcinoma: The european prospective investigation into cancer and nutrition. Int. J. Cancer 2014, 135, 1662–1672.
200. Melnik, B.C. MiR-21: An environmental driver of malignant melanoma? J. Transl. Med. 2015, doi:10.1186/s12967-015-0570-5.
201. Meng, F.; Henson, R.; Wehbe-Janek, H.; Ghoshal, K.; Jacob, S.T.; Patel, T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 2007, 133, 647–658.
202. Olivieri, F.; Spazzafumo, L.; Santini, G.; Lazzarini, R.; Albertini, M.C.; Rippo, M.R.; Galeazzi, R.; Abbatecola, A.M.; Marcheselli, F.; Monti, D. et al. Age-related differences in the expression of circulating microRNAs: miR-21 as a new circulating marker of inflammaging. Mech. Ageing Dev. 2012, 133, 675–685.
203. Melnik, B.C.; John, S.M.; Schmitz, G. Milk is not just food but most likely a genetic transfection system activating mTORC1 signaling for postnatal growth. Nutr. J. 2013, doi:10.1186/1475-2891-12-103.
204. Kim, Y.J.; Hwang, S.J.; Bae, Y.C.; Jung, J.S. MiR-21 regulates adipogenic differentiation through the modulation of TGF-beta signaling in mesenchymal stem cells derived from human adipose tissue. Stem Cells 2009, 27, 3093–3102.
205. Hammond, S.M. MicroRNAs as tumor suppressors. Nat. Genet. 2007, 39, 582–583.
206. Johnson, S.M.; Grosshans, H.; Shingara, J.; Byrom, M.; Jarvis, R.; Cheng, A.; Labourier, E.; Reinert, K.L.; Brown, D.; Slack, F.J. RAS is regulated by the let-7 microRNA family. Cell 2005, 120, 635–647.
207. Miller, E.M.; Aiello, M.O.; Fujita, M.; Hinde, K.; Milligan, L.; Quinn, E.A. Field and laboratory methods in human milk research. Am. J. Hum. Biol. 2013, 25, 1–11.
208. Hassiotou, F.; Hartmann, P.E. At the dawn of a new discovery: The potential of breast milk stem cells. Adv. Nutr. 2014, 5, 770–778.
209. Melnik, B.C. Milk—A Nutrient System of Mammalian Evolution Promoting mTORC1-Dependent Translation. Int. J. Mol. Sci. 2015, 16, 17048–17087.
210. Greer, F.R.; Sicherer, S.H.; Burks, A.W.; American Academy of Pediatrics. Effects of early nutritional interventions on the development of atopic disease in infants and children: The role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics 2008, 121, 183-191.
211. Fein, S.B.; Falci, C.D. Infant formula preparation, handling, and related practices in the United States. J. Am. Diet. Assoc. 1999, 99, 1234–1240.
212. Cregan, M.D.; Fan, Y.; Appelbee, A.; Brown, M.L.; Klopcic, B.; Koppen, J.; Mitoulas, L.R.; Piper, K.M.; Choolani, M.A.; Chong, Y.S. et al. Identification of nestin-positive putative mammary stem cells in human breastmilk. Cell Tissue Res. 2007, 329, 129–136.
213. Verduci, E.; Banderali, G.; Barberi, S.; Radaelli, G.; Lops, A.; Betti, F.; Riva, E.; Giovannini, M. Epigenetic effects of human breast milk. Nutrients 2014, 6, 1711–1724.
214. Bode, L.; McGuire, M.; Rodriguez, J.M.; Geddes, D.T.; Hassiotou, F.; Hartmann, P.E.; McGuire, M.K. It’s alive: Microbes and cells in human milk and their potential benefits to mother and infant. Adv. Nutr. 2014, 5, 571–573.
215. Food and Drug Administration, Department of Health & Human Services. Current good manufacturing practices, quality control procedures, quality factors, notification requirements, and records and reports, for infant formula. Fed. Regist. 2014, 79, 33057–33072.
216. Gigli, I.; Maizon, D.O. microRNAs and the mammary gland: A new understanding of gene expression. Genet. Mol. Biol. 2013, 36, 465–474.
217. Melnik, B.C.; John, S.M.; Schmitz, G. Milk: An exosomal microRNA transmitter promoting thymic regulatory T cell maturation preventing the development of atopy? J. Transl. Med. 2014, doi:10.1186/1479-5876-12-43.
218. Xiao, J.; Zhu, X.; He, B.; Zhang, Y.; Kang, B.; Wang, Z.; Ni, X. MiR-204 regulates cardiomyocyte autophagy induced by ischemia-reperfusion through LC3-II. J. Biomed. Sci. 2011, 18, 35, doi:10.1186/1423-0127-18-35.
219. Blenkiron, C.; Miska, E. A. miRNAs in cancer: Approaches, aetiology, diagnostics and therapy. Hum. Mol. Genet. 2007, doi:10.1093/hmg/ddm056.
220. Heneghan, H.M.; Miller, N.; Lowery, A.J.; Sweeney, K.J.; Kerin, M.J. MicroRNAs as novel biomarkers for breast cancer. J. Oncol. 2009, doi:10.1155/2010/950201.
221. 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.