Availability of Circulating MicroRNAs as a Biomarker for Early Diagnosis of Diffuse Large B-Cell Lymphoma
Author(s)
Katsushige Inada1*,
Yasushi Okoshi1,2,3,
Yukiko Cho4,
Hitoaki Saito5,
Tatsuo Iijima5,
Mitsuo Hori1,
Hiroshi Kojima2,3,4
Affiliation(s)
1 Department of Hematology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan. 2 Ibaraki Clinical Education and Training Center, University of Tsukuba Hospital, Ibaraki, Japan. 3 Faculty of Medicine, University of Tsukuba, Ibaraki, Japan. 4 Department of Medical Oncology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan. 5 Department of Pathology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan.
1 Department of Hematology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan. 2 Ibaraki Clinical Education and Training Center, University of Tsukuba Hospital, Ibaraki, Japan. 3 Faculty of Medicine, University of Tsukuba, Ibaraki, Japan. 4 Department of Medical Oncology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan. 5 Department of Pathology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan.
ABSTRACT
Background: MicroRNA (miRNA) regulates post-transcriptional gene expression through binding to complementary sites of target messenger RNA, including that from oncogenes or tumor suppressor genes. This study planned to pursue the possibility that circulating miRNA could be used for the early diagnosis of diffuse large B-cell lymphoma (DLBCL). Materials and Methods: Expression levels of miRNA obtained from serum, exosome-enriched serum, and formalin-fixed paraffin-embedded (FFPE) tissue were evaluated. Samples were collected from patients with newly diagnosed DLBCL (n = 33) or healthy volunteers (n = 22). Based on the results of previous reports, ten miRNAs were selected and expression levels were analyzed by the quantitative real-time PCR. Results: The expression levels of hsa-miR-15a-3p, hsa-miR-21-5p, hsa-miR-181a-5p, and hsa-miR-210-5p differed significantly between DLBCL patients and controls in serum and/or exosome-enriched serum, but not in FFPE tissue. In contrast, expression levels of hsa-miR-155-5p in FFPE tissue were significantly higher in DLBCL patients, as previously reported. Conclusion: We confirmed that some miRNAs were differentially expressed in serum from DLBCL patients as previously reported. Measurement of these miRNA in exosome-enriched serum did not improve the accuracy in the differential diagnosis of DLBCL. In addition, these miRNAs seem to be produced outside of lymphoma tissue.
Background: MicroRNA (miRNA) regulates post-transcriptional gene expression through binding to complementary sites of target messenger RNA, including that from oncogenes or tumor suppressor genes. This study planned to pursue the possibility that circulating miRNA could be used for the early diagnosis of diffuse large B-cell lymphoma (DLBCL). Materials and Methods: Expression levels of miRNA obtained from serum, exosome-enriched serum, and formalin-fixed paraffin-embedded (FFPE) tissue were evaluated. Samples were collected from patients with newly diagnosed DLBCL (n = 33) or healthy volunteers (n = 22). Based on the results of previous reports, ten miRNAs were selected and expression levels were analyzed by the quantitative real-time PCR. Results: The expression levels of hsa-miR-15a-3p, hsa-miR-21-5p, hsa-miR-181a-5p, and hsa-miR-210-5p differed significantly between DLBCL patients and controls in serum and/or exosome-enriched serum, but not in FFPE tissue. In contrast, expression levels of hsa-miR-155-5p in FFPE tissue were significantly higher in DLBCL patients, as previously reported. Conclusion: We confirmed that some miRNAs were differentially expressed in serum from DLBCL patients as previously reported. Measurement of these miRNA in exosome-enriched serum did not improve the accuracy in the differential diagnosis of DLBCL. In addition, these miRNAs seem to be produced outside of lymphoma tissue.
Cite this paper
Inada, K. , Okoshi, Y. , Cho, Y. , Saito, H. , Iijima, T. , Hori, M. , Kojima, H. , (2015) Availability of Circulating MicroRNAs as a Biomarker for Early Diagnosis of Diffuse Large B-Cell Lymphoma. Open Journal of Blood Diseases, 5, 48-58. doi: 10.4236/ojbd.2015.54008.
Inada, K. , Okoshi, Y. , Cho, Y. , Saito, H. , Iijima, T. , Hori, M. , Kojima, H. , (2015) Availability of Circulating MicroRNAs as a Biomarker for Early Diagnosis of Diffuse Large B-Cell Lymphoma. Open Journal of Blood Diseases, 5, 48-58. doi: 10.4236/ojbd.2015.54008.
References
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http://dx.doi.org/10.1073/pnas.0804549105 [3] Kosaka, N., Iguchi, H. and Ochiya, T. (2010) Circulating MicroRNA in Body Fluid: A New Potential Biomarker for Cancer Diagnosis and Prognosis. Cancer Science, 101, 2087-2092.
http://dx.doi.org/10.1111/j.1349-7006.2010.01650.x [4] Sundarbose, K., Kartha, R. and Subramanian, S. (2013) MicroRNAs as Biomarkers in Cancer. Diagnostics, 3, 84-104. http://dx.doi.org/10.3390/diagnostics3010084 [5] Valadi, H., Ekstrom, K., Bossios, A., Sjostrand, M., Lee, J.J. and Lotvall, J.O. (2007) Exosome-Mediated Transfer of mRNAs and MicroRNAs is a Novel Mechanism of Genetic Exchange between Cells. Nature Cell Biology, 9, 654-659. http://dx.doi.org/10.1038/ncb1596 [6] Arroyo, J.D., Chevillet J.R., Kroh E.M., Ruf I.K., Pritchard C.C., Gibson D.F., Mitchell P.S., Bennett C.F., Pogosova-Agadjanyan E.L., Stirewalt D.L., Tait J.F. and Tewari M. (2011) Argonaute2 complexes carry a population of circulating MicroRNAs Independent of Vesicles in Human Plasma. Proceedings of the National Academy of Sciences of the United States of America, 108, 5003-5008.
http://dx.doi.org/10.1073/pnas.1019055108 [7] Moller, M.B., Pedersen, N.T. and Christensen, B.E. (2004) Diffuse Large B-Cell Lymphoma: Clinical Implications of Extranodal versus Nodal Presentation—A Population-Based Study of 1575 Cases. British Journal of Haematology, 124, 151-159. http://dx.doi.org/10.1046/j.1365-2141.2003.04749.x [8] Lopez-Guillermo, A., Colomo, L., Jimenez, M., Bosch, F., Villamor, N., Arenillas, L., Muntanola, A., Montoto, S., Gine, E., Colomer, D., Bea, S., Campo, E. and Montserrat, E. (2005) Diffuse Large B-Cell Lymphoma: Clinical and Biological Characterization and Outcome According to the Nodal or Extranodal Primary Origin. Journal of Clinical Oncology, 23, 2797-2804. http://dx.doi.org/10.1200/JCO.2005.07.155 [9] Lawrie, C.H., Gal, S., Dunlop, H.M., Pushkaran, B., Liggins, A.P., Pulford, K., Banham, A.H., Pezzella, F., Boultwood, J., Wainscoat, J.S., Hatton, C.S. and Harris, A.L. (2008) Detection of Elevated Levels of Tumour-Associated MicroRNAs in Serum of Patients with Diffuse Large B-Cell Lymphoma. British Journal of Haematology, 141, 672-675. http://dx.doi.org/10.1111/j.1365-2141.2008.07077.x [10] Fang, C., Zhu, D.X., Dong, H.J., Zhou, Z.J., Wang, Y.H., Liu, L., Fan, L., Miao, K.R., Liu, P., Xu, W. and Li, J.Y. (2012) Serum MicroRNAs Are Promising Novel Biomarkers for Diffuse Large B Cell Lymphoma. Annals of Hematology, 91, 553-559. http://dx.doi.org/10.1007/s00277-011-1350-9 [11] Baraniskin, A., Kuhnhenn, J., Schlegel, U., Chan, A., Deckert, M., Gold, R., Maghnouj, A., Zollner, H., Reinacher-Schick, A., Schmiegel, W., Hahn, S.A. and Schroers, R. (2011) Identification of MicroRNAs in the Cerebrospinal Fluid as Marker for Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System. Blood, 117, 3140-3146. http://dx.doi.org/10.1182/blood-2010-09-308684 [12] Alencar, A.J., Malumbres, R., Kozloski, G.A., Advani, R., Talreja, N., Chinichian, S., Briones, J., Natkunam, Y., Sehn, L.H., Gascoyne, R.D., Tibshirani, R. and Lossos, I.S. (2011) MicroRNAs Are Independent Predictors of Outcome in Diffuse Large B-Cell Lymphoma Patients Treated with R-Chop. Clinical Cancer Research, 17, 4125-4135. http://dx.doi.org/10.1158/1078-0432.CCR-11-0224 [13] Zhong, H., Xu, L., Zhong, J.H., Xiao, F., Liu, Q., Huang, H.H. and Chen, F.Y. (2012) Clinical and Prognostic Significance of miR-155 and miR-146a Expression Levels in Formalin-Fixed/Paraffin-Embedded Tissue of Patients with Diffuse Large B-Cell Lymphoma. Experimental and Therapeutic Medicine, 3, 763-770. [14] Culpin, R.E., Sieniawski, M., Proctor, S.J., Menon, G. and Mainou-Fowler, T. (2013) MicroRNAs Are Suitable for Assessment as Biomarkers from Formalin-Fixed Paraffin-Embedded Tissue, and miR-24 Represents an Appropriate Reference MicroRNA for Diffuse Large B-Cell Lymphoma Studies. Journal of Clinical Pathology, 66, 249-252. http://dx.doi.org/10.1136/jclinpath-2012-201021 [15] Lawrie, C.H., Soneji, S., Marafioti, T., Cooper, C.D., Palazzo, S., Paterson, J.C., Cattan, H., Enver, T., Mager, R., Boultwood, J., Wainscoat, J.S. and Hatton, C.S. (2007) MicroRNA Expression Distinguishes between Germinal Center B Cell-Like and Activated B Cell-Like Subtypes of Diffuse Large B Cell Lymphoma. International Journal of Cancer, 121, 1156-1161. http://dx.doi.org/10.1002/ijc.22800 [16] Xu, L., Yang, B.F. and Ai, J. (2013) MicroRNA Transport: A New Way in Cell Communication. Journal of Cellular Physiology, 228, 1713-1719. http://dx.doi.org/10.1002/jcp.24344 [17] Kosaka, N., Iguchi, H., Yoshioka, Y., Takeshita, F., Matsuki, Y. and Ochiya, T. (2010) Secretory Mechanisms and Intercellular Transfer of MicroRNAs in Living Cells. The Journal of Biological Chemistry, 285, 17442-17452. http://dx.doi.org/10.1074/jbc.M110.107821 [18] Yoshioka, Y., Kosaka, N., Konishi, Y., Ohta, H., Okamoto, H., Sonoda, H., Nonaka, R., Yamamoto, H., Ishii, H., Mori, M., Furuta, K., Nakajima, T., Hayashi, H., Sugisaki, H., Higashimoto, H., Kato, T., Takeshita, F. and Ochiya, T. (2014) Ultra-Sensitive Liquid Biopsy of Circulating Extracellular Vesicles Using ExoScreen. Nature Communications, 5, Article No. 3591. http://dx.doi.org/10.1038/ncomms4591 [19] Xi, Y., Nakajima, G., Gavin, E., Morris, C.G., Kudo, K., Hayashi, K. and Ju, J. (2007) Systematic Analysis of MicroRNA Expression of RNA Extracted from Fresh Frozen and Formalin-Fixed Paraffin-Embedded Samples. RNA, 13, 1668-1674. http://dx.doi.org/10.1261/rna.642907 [20] Li, J., Smyth, P., Flavin, R., Cahill, S., Denning, K., Aherne, S., Guenther, S.M., O’Leary, J.J. and Sheils, O. (2007) Comparison of miRNA Expression Patterns Using Total RNA Extracted from Matched Samples of Formalin-Fixed Paraffin-Embedded (FFPE) Cells and Snap Frozen Cells. BMC Biotechnology, 7, 36.
http://dx.doi.org/10.1186/1472-6750-7-36 [21] Munch-Petersen, H.D., Ralfkiaer, U., Sjo, L.D., Hother, C., Asmar, F., Nielsen, B.S., Brown, P., Ralfkiaer, E. and Gronbaek, K. (2015) Differential Expression of miR-155 and miR-21 in Tumor and Stroma Cells in Diffuse Large B-Cell Lymphoma. Applied Immunohistochemistry & Molecular Morphology, 23, 188-195.
http://dx.doi.org/10.1097/PAI.0000000000000073 [22] Kosaka, N., Iguchi, H., Yoshioka, Y., Hagiwara, K., Takeshita, F. and Ochiya, T. (2012) Competitive Interactions of Cancer Cells and Normal Cells via Secretory MicroRNAs. The Journal of Biological Chemistry, 287, 1397-1405. http://dx.doi.org/10.1074/jbc.M111.288662 [23] Qin, Q., Wei, F.R. and Li, B.S. (2014) Multiple Functions of Hypoxia-Regulated miR-210 in Cancer. Journal of Experimental & Clinical Cancer Research, 33, 50. http://dx.doi.org/10.1186/1756-9966-33-50 [24] Volinia, S., Calin, G.A., Liu, C.G., Ambs, S., Cimmino, A., Petrocca, F., Visone, R., Iorio, M., Roldo, C., Ferracin, M., Prueitt, R.L., Yanaihara, N., Lanza, G., Scarpa, A., Vecchione, A., Negrini, M., Harris, C.C. and Croce, C.M. (2006) A MicroRNA Expression Signature of Human Solid Tumors Defines Cancer Gene Targets. Proceedings of the National Academy of Sciences of the United States of America, 103, 2257-2261. http://dx.doi.org/10.1073/pnas.0510565103 [25] Aqeilan, R.I., Calin, G.A. and Croce, C.M. (2010) MiR-15a and miR-16-1 in Cancer: Discovery, Function and Future Perspectives. Cell Death and Differentiation, 17, 215-220.
http://dx.doi.org/10.1038/cdd.2009.69 [26] Li, H., Hui, L. and Xu, W. (2012) MiR-181a Sensitizes a Multidrug-Resistant Leukemia Cell Line K562/A02 to Daunorubicin by Targeting BCL-2. Acta Biochimica et Biophysica Sinica, 44, 269-277.
http://dx.doi.org/10.1093/abbs/gmr128 [27] Neilson, J.R., Zheng, G.X., Burge, C.B. and Sharp, P.A. (2007) Dynamic Regulation of miRNA Expression in Ordered Stages of Cellular Development. Genes & Development, 21, 578-589.
http://dx.doi.org/10.1101/gad.1522907 [28] Wickramasinghe, N.S., Manavalan, T.T., Dougherty, S.M., Riggs, K.A., Li, Y. and Klinge, C.M. (2009) Estradiol Downregulates miR-21 Expression and Increases miR-21 Target Gene Expression in MCF-7 Breast Cancer Cells. Nucleic Acids Research, 37, 2584-2595. http://dx.doi.org/10.1093/nar/gkp117 [29] Kelly, P.N. and Strasser, A. (2011) The Role of BCL-2 and Its Pro-Survival Relatives in Tumourigenesis and Cancer Therapy. Cell Death and Differentiation, 18, 1414-1424.
http://dx.doi.org/10.1038/cdd.2011.17 [30] Meng, F., Henson, R., Wehbe-Janek, H., Ghoshal, K., Jacob, S.T. and Patel, T. (2007) MicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular Cancer. Gastroenterology, 133, 647-658. http://dx.doi.org/10.1053/j.gastro.2007.05.022 [31] Weiland, M., Gao, X.H., Zhou, L. and Mi, Q.S. (2012) Small RNAs Have a Large Impact: Circulating MicroRNAs as Biomarkers for Human Diseases. RNA Biology, 9, 850-859.
http://dx.doi.org/10.4161/rna.20378
[1] Gregory, R.I. and Shiekhattar, R. (2005) MicroRNA Biogenesis and Cancer. Cancer Research, 65, 3509-3512. http://dx.doi.org/10.1158/0008-5472.CAN-05-0298 [2] 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., Lin, D.W., Urban, N., Drescher, C.W., Knudsen, B.S., Stirewalt, D.L., Gentleman, R., Vessella, R.L., Nelson, P.S., Martin, D.B. and Tewari M. (2008) Circulating MicroRNAs as Stable Blood-Based Markers for Cancer Detection. Proceedings of the National Academy of Sciences of the United States of America, 105, 10513-10518.
http://dx.doi.org/10.1073/pnas.0804549105 [3] Kosaka, N., Iguchi, H. and Ochiya, T. (2010) Circulating MicroRNA in Body Fluid: A New Potential Biomarker for Cancer Diagnosis and Prognosis. Cancer Science, 101, 2087-2092.
http://dx.doi.org/10.1111/j.1349-7006.2010.01650.x [4] Sundarbose, K., Kartha, R. and Subramanian, S. (2013) MicroRNAs as Biomarkers in Cancer. Diagnostics, 3, 84-104. http://dx.doi.org/10.3390/diagnostics3010084 [5] Valadi, H., Ekstrom, K., Bossios, A., Sjostrand, M., Lee, J.J. and Lotvall, J.O. (2007) Exosome-Mediated Transfer of mRNAs and MicroRNAs is a Novel Mechanism of Genetic Exchange between Cells. Nature Cell Biology, 9, 654-659. http://dx.doi.org/10.1038/ncb1596 [6] Arroyo, J.D., Chevillet J.R., Kroh E.M., Ruf I.K., Pritchard C.C., Gibson D.F., Mitchell P.S., Bennett C.F., Pogosova-Agadjanyan E.L., Stirewalt D.L., Tait J.F. and Tewari M. (2011) Argonaute2 complexes carry a population of circulating MicroRNAs Independent of Vesicles in Human Plasma. Proceedings of the National Academy of Sciences of the United States of America, 108, 5003-5008.
http://dx.doi.org/10.1073/pnas.1019055108 [7] Moller, M.B., Pedersen, N.T. and Christensen, B.E. (2004) Diffuse Large B-Cell Lymphoma: Clinical Implications of Extranodal versus Nodal Presentation—A Population-Based Study of 1575 Cases. British Journal of Haematology, 124, 151-159. http://dx.doi.org/10.1046/j.1365-2141.2003.04749.x [8] Lopez-Guillermo, A., Colomo, L., Jimenez, M., Bosch, F., Villamor, N., Arenillas, L., Muntanola, A., Montoto, S., Gine, E., Colomer, D., Bea, S., Campo, E. and Montserrat, E. (2005) Diffuse Large B-Cell Lymphoma: Clinical and Biological Characterization and Outcome According to the Nodal or Extranodal Primary Origin. Journal of Clinical Oncology, 23, 2797-2804. http://dx.doi.org/10.1200/JCO.2005.07.155 [9] Lawrie, C.H., Gal, S., Dunlop, H.M., Pushkaran, B., Liggins, A.P., Pulford, K., Banham, A.H., Pezzella, F., Boultwood, J., Wainscoat, J.S., Hatton, C.S. and Harris, A.L. (2008) Detection of Elevated Levels of Tumour-Associated MicroRNAs in Serum of Patients with Diffuse Large B-Cell Lymphoma. British Journal of Haematology, 141, 672-675. http://dx.doi.org/10.1111/j.1365-2141.2008.07077.x [10] Fang, C., Zhu, D.X., Dong, H.J., Zhou, Z.J., Wang, Y.H., Liu, L., Fan, L., Miao, K.R., Liu, P., Xu, W. and Li, J.Y. (2012) Serum MicroRNAs Are Promising Novel Biomarkers for Diffuse Large B Cell Lymphoma. Annals of Hematology, 91, 553-559. http://dx.doi.org/10.1007/s00277-011-1350-9 [11] Baraniskin, A., Kuhnhenn, J., Schlegel, U., Chan, A., Deckert, M., Gold, R., Maghnouj, A., Zollner, H., Reinacher-Schick, A., Schmiegel, W., Hahn, S.A. and Schroers, R. (2011) Identification of MicroRNAs in the Cerebrospinal Fluid as Marker for Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System. Blood, 117, 3140-3146. http://dx.doi.org/10.1182/blood-2010-09-308684 [12] Alencar, A.J., Malumbres, R., Kozloski, G.A., Advani, R., Talreja, N., Chinichian, S., Briones, J., Natkunam, Y., Sehn, L.H., Gascoyne, R.D., Tibshirani, R. and Lossos, I.S. (2011) MicroRNAs Are Independent Predictors of Outcome in Diffuse Large B-Cell Lymphoma Patients Treated with R-Chop. Clinical Cancer Research, 17, 4125-4135. http://dx.doi.org/10.1158/1078-0432.CCR-11-0224 [13] Zhong, H., Xu, L., Zhong, J.H., Xiao, F., Liu, Q., Huang, H.H. and Chen, F.Y. (2012) Clinical and Prognostic Significance of miR-155 and miR-146a Expression Levels in Formalin-Fixed/Paraffin-Embedded Tissue of Patients with Diffuse Large B-Cell Lymphoma. Experimental and Therapeutic Medicine, 3, 763-770. [14] Culpin, R.E., Sieniawski, M., Proctor, S.J., Menon, G. and Mainou-Fowler, T. (2013) MicroRNAs Are Suitable for Assessment as Biomarkers from Formalin-Fixed Paraffin-Embedded Tissue, and miR-24 Represents an Appropriate Reference MicroRNA for Diffuse Large B-Cell Lymphoma Studies. Journal of Clinical Pathology, 66, 249-252. http://dx.doi.org/10.1136/jclinpath-2012-201021 [15] Lawrie, C.H., Soneji, S., Marafioti, T., Cooper, C.D., Palazzo, S., Paterson, J.C., Cattan, H., Enver, T., Mager, R., Boultwood, J., Wainscoat, J.S. and Hatton, C.S. (2007) MicroRNA Expression Distinguishes between Germinal Center B Cell-Like and Activated B Cell-Like Subtypes of Diffuse Large B Cell Lymphoma. International Journal of Cancer, 121, 1156-1161. http://dx.doi.org/10.1002/ijc.22800 [16] Xu, L., Yang, B.F. and Ai, J. (2013) MicroRNA Transport: A New Way in Cell Communication. Journal of Cellular Physiology, 228, 1713-1719. http://dx.doi.org/10.1002/jcp.24344 [17] Kosaka, N., Iguchi, H., Yoshioka, Y., Takeshita, F., Matsuki, Y. and Ochiya, T. (2010) Secretory Mechanisms and Intercellular Transfer of MicroRNAs in Living Cells. The Journal of Biological Chemistry, 285, 17442-17452. http://dx.doi.org/10.1074/jbc.M110.107821 [18] Yoshioka, Y., Kosaka, N., Konishi, Y., Ohta, H., Okamoto, H., Sonoda, H., Nonaka, R., Yamamoto, H., Ishii, H., Mori, M., Furuta, K., Nakajima, T., Hayashi, H., Sugisaki, H., Higashimoto, H., Kato, T., Takeshita, F. and Ochiya, T. (2014) Ultra-Sensitive Liquid Biopsy of Circulating Extracellular Vesicles Using ExoScreen. Nature Communications, 5, Article No. 3591. http://dx.doi.org/10.1038/ncomms4591 [19] Xi, Y., Nakajima, G., Gavin, E., Morris, C.G., Kudo, K., Hayashi, K. and Ju, J. (2007) Systematic Analysis of MicroRNA Expression of RNA Extracted from Fresh Frozen and Formalin-Fixed Paraffin-Embedded Samples. RNA, 13, 1668-1674. http://dx.doi.org/10.1261/rna.642907 [20] Li, J., Smyth, P., Flavin, R., Cahill, S., Denning, K., Aherne, S., Guenther, S.M., O’Leary, J.J. and Sheils, O. (2007) Comparison of miRNA Expression Patterns Using Total RNA Extracted from Matched Samples of Formalin-Fixed Paraffin-Embedded (FFPE) Cells and Snap Frozen Cells. BMC Biotechnology, 7, 36.
http://dx.doi.org/10.1186/1472-6750-7-36 [21] Munch-Petersen, H.D., Ralfkiaer, U., Sjo, L.D., Hother, C., Asmar, F., Nielsen, B.S., Brown, P., Ralfkiaer, E. and Gronbaek, K. (2015) Differential Expression of miR-155 and miR-21 in Tumor and Stroma Cells in Diffuse Large B-Cell Lymphoma. Applied Immunohistochemistry & Molecular Morphology, 23, 188-195.
http://dx.doi.org/10.1097/PAI.0000000000000073 [22] Kosaka, N., Iguchi, H., Yoshioka, Y., Hagiwara, K., Takeshita, F. and Ochiya, T. (2012) Competitive Interactions of Cancer Cells and Normal Cells via Secretory MicroRNAs. The Journal of Biological Chemistry, 287, 1397-1405. http://dx.doi.org/10.1074/jbc.M111.288662 [23] Qin, Q., Wei, F.R. and Li, B.S. (2014) Multiple Functions of Hypoxia-Regulated miR-210 in Cancer. Journal of Experimental & Clinical Cancer Research, 33, 50. http://dx.doi.org/10.1186/1756-9966-33-50 [24] Volinia, S., Calin, G.A., Liu, C.G., Ambs, S., Cimmino, A., Petrocca, F., Visone, R., Iorio, M., Roldo, C., Ferracin, M., Prueitt, R.L., Yanaihara, N., Lanza, G., Scarpa, A., Vecchione, A., Negrini, M., Harris, C.C. and Croce, C.M. (2006) A MicroRNA Expression Signature of Human Solid Tumors Defines Cancer Gene Targets. Proceedings of the National Academy of Sciences of the United States of America, 103, 2257-2261. http://dx.doi.org/10.1073/pnas.0510565103 [25] Aqeilan, R.I., Calin, G.A. and Croce, C.M. (2010) MiR-15a and miR-16-1 in Cancer: Discovery, Function and Future Perspectives. Cell Death and Differentiation, 17, 215-220.
http://dx.doi.org/10.1038/cdd.2009.69 [26] Li, H., Hui, L. and Xu, W. (2012) MiR-181a Sensitizes a Multidrug-Resistant Leukemia Cell Line K562/A02 to Daunorubicin by Targeting BCL-2. Acta Biochimica et Biophysica Sinica, 44, 269-277.
http://dx.doi.org/10.1093/abbs/gmr128 [27] Neilson, J.R., Zheng, G.X., Burge, C.B. and Sharp, P.A. (2007) Dynamic Regulation of miRNA Expression in Ordered Stages of Cellular Development. Genes & Development, 21, 578-589.
http://dx.doi.org/10.1101/gad.1522907 [28] Wickramasinghe, N.S., Manavalan, T.T., Dougherty, S.M., Riggs, K.A., Li, Y. and Klinge, C.M. (2009) Estradiol Downregulates miR-21 Expression and Increases miR-21 Target Gene Expression in MCF-7 Breast Cancer Cells. Nucleic Acids Research, 37, 2584-2595. http://dx.doi.org/10.1093/nar/gkp117 [29] Kelly, P.N. and Strasser, A. (2011) The Role of BCL-2 and Its Pro-Survival Relatives in Tumourigenesis and Cancer Therapy. Cell Death and Differentiation, 18, 1414-1424.
http://dx.doi.org/10.1038/cdd.2011.17 [30] Meng, F., Henson, R., Wehbe-Janek, H., Ghoshal, K., Jacob, S.T. and Patel, T. (2007) MicroRNA-21 Regulates Expression of the PTEN Tumor Suppressor Gene in Human Hepatocellular Cancer. Gastroenterology, 133, 647-658. http://dx.doi.org/10.1053/j.gastro.2007.05.022 [31] Weiland, M., Gao, X.H., Zhou, L. and Mi, Q.S. (2012) Small RNAs Have a Large Impact: Circulating MicroRNAs as Biomarkers for Human Diseases. RNA Biology, 9, 850-859.
http://dx.doi.org/10.4161/rna.20378