微小核醣核酸是一段由體內自行合成的小片段RNA序列，藉由translation repression或mRNA cleavage來抑制基因的表現。MiR-182為miR-96,182,183 cluster的一員，座落在chromosome 7q32的區域並且在許多癌症中有高度表現。最近的研究顯示miR-182主要扮演oncogenic miRNA並且會抑制數種tumor suppressor genes像是FOXO3, FOXO1, BRCA1 與MTSS1等。在本篇的第一部分研究中，我們驗證miR-182高度表現在乳癌病人檢體及細胞株內，此外，我們發現在乳癌細胞株內β-catenin可以去調控miR-182，在MDA-MB-231抑制或knockdown β-catenin的情況下均會顯著的降低miR-182的表現。Chromatin immunoprecipitation assay證明β-catenin會結合到miR-182的啟動子上。我們進一步的找到tumor suppressor genes-RECK為miR-182新的標的基因，在MDA-MB-231轉殖anti-miR-182會增加RECK蛋白質的表現，而在人類乳腺上皮細胞H184B5F5/M10轉殖pre-miR-182則會抑制RECK蛋白質的表現，但在上述的情況下均不會去影響RECK mRNA的表現。利用anti-miR-182增加RECK蛋白質的表現下會進而去抑制下游的間質金屬酶9的活性、細胞侵犯與群落形成的能力，更重要的是，表現miR-182的情況下會去抑制β-catenin inhibitor所造成RECK蛋白質回升的現象，意味著miR-182是β-catenin調控RECK的重要中間者。綜合上述的結果，我們證明了在乳癌內β-catenin會去調控miR-182且miR-182會去抑制RECK蛋白質的表現，進而增加間質金屬酶9的活性與細胞侵犯的能力。

MicroRNAs (MiRNAs) are endogenous small non-coding RNAs which negatively regulate gene expression by inducing translation repression or mRNA cleavage. MiR-182 is a member of the miR-183 cluster which is located at human chromosome 7q32 region and is over-expressed in several types of human cancer. Recent studies demonstrated that miR-182 functions as an oncogenic miRNA via inhibition of several tumor suppressor genes like FOXO3, FOXO1, BRCA1 and MTSS1. In the first part of this study, we demonstrated that miR-182 is over-expressed in human breast tumor tissues and cell lines. In addition, we found that β-catenin up-regulated miR-182 expression in breast cancer cells. Inhibition or knockdown of β-catenin significantly reduced miR-182 level in MDA-MB-231 cells. Chromatin immunoprecipitation assay confirmed the constitutive binding of β-catenin on miR-182 promoter. We further identified the tumor suppressor Reversion-inducing Cysteine-rich Protein with Kazal motifs (RECK) as a new target of miR-182. Anti-miR-182 increased RECK protein in MDA-MB-231 cells while pre-miR-182 reduced RECK protein but not mRNA in H184B5F5/M10 human normal mammary epithelial cells. Restoration of RECK protein by anti-miR-182 attenuated matrix metalloproteinase-9 (MMP-9) activity, cell invasion and colony formation. More importantly, ectopic expression of miR-182 inhibited restoration of RECK protein by β-catenin inhibitor indicating induction of miR-182 is important for β-catenin-induced down-regulation of RECK. Taken together, we provide evidences that miR-182 is up-regulated by β-catenin signaling pathway in breast cancer and its up-regulation increases MMP-9 activity and cell invasiveness by repressing RECK.

Part I Up-regulation of miR-182 by β-catenin in breast cancer increases invasiveness by targeting the matrix metalloproteinase inhibitor RECK
1. Introduction………………………………………………………………………...1
2. Specific aim………………………………………………………………………..10
3. Materials…………………………………………………………………...............11
4. Methods……………………………………………………………………………14
5. Results……………………………………………………………………...............26
6. Figures and tables…………………………………………………………………33
7. Discussion………………………………………………………………………….50
8. Appendix…………………………………………………………………………...54
Part II The role of miR-182 in chemokine expression
1. Introduction……………………………………………………………………….62
2. Materials…………………………………………………………………...............65
3. Methods……………………………………………………………………………66
4. Preliminary results………………………………………………………………..67
5. Figures…………………………………………………………………………....68
6. Discussion………………………………………………………………………….72
7. Appendix……………………………………………………………………….…..74
8. References………………………………………………………………………….78
9. Curriculum Vitae……………………………………………………………..…...91

[1] A. Esquela-Kerscher, F.J. Slack, Oncomirs - microRNAs with a role in cancer, Nat Rev Cancer, 6 (2006) 259-269.
[2] V.N. Kim, MicroRNA biogenesis: coordinated cropping and dicing, Nat Rev Mol Cell Biol, 6 (2005) 376-385.
[3] R. Garzon, G. Marcucci, C.M. Croce, Targeting microRNAs in cancer: rationale, strategies and challenges, Nat Rev Drug Discov, 9 (2010) 775-789.
[4] D.P. Bartel, MicroRNAs: genomics, biogenesis, mechanism, and function, Cell, 116 (2004) 281-297.
[5] I. Alvarez-Garcia, E.A. Miska, MicroRNA functions in animal development and human disease, Development, 132 (2005) 4653-4662.
[6] G. Stefani, F.J. Slack, Small non-coding RNAs in animal development, Nat Rev Mol Cell Biol, 9 (2008) 219-230.
[7] V. Ambros, The functions of animal microRNAs, Nature, 431 (2004) 350-355.
[8] G.A. Calin, C. Sevignani, C.D. Dumitru, T. Hyslop, E. Noch, S. Yendamuri, M. Shimizu, S. Rattan, F. Bullrich, M. Negrini, C.M. Croce, Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers, Proc Natl Acad Sci U S A, 101 (2004) 2999-3004.
[9] B. Zhang, X. Pan, G.P. Cobb, T.A. Anderson, microRNAs as oncogenes and tumor suppressors, Dev Biol, 302 (2007) 1-12.
[10] G.A. Calin, C.D. Dumitru, M. Shimizu, R. Bichi, S. Zupo, E. Noch, H. Aldler, S. Rattan, M. Keating, K. Rai, L. Rassenti, T. Kipps, M. Negrini, F. Bullrich, C.M. Croce, Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia, Proc Natl Acad Sci U S A, 99 (2002) 15524-15529.
[11] A. Cimmino, G.A. Calin, M. Fabbri, M.V. Iorio, M. Ferracin, M. Shimizu, S.E. Wojcik, R.I. Aqeilan, S. Zupo, M. Dono, L. Rassenti, H. Alder, S. Volinia, C.G. Liu, T.J. Kipps, M. Negrini, C.M. Croce, miR-15 and miR-16 induce apoptosis by targeting BCL2, Proc Natl Acad Sci U S A, 102 (2005) 13944-13949.
[12] G.A. Calin, M. Ferracin, A. Cimmino, G. Di Leva, M. Shimizu, S.E. Wojcik, M.V. Iorio, R. Visone, N.I. Sever, M. Fabbri, R. Iuliano, T. Palumbo, F. Pichiorri, C. Roldo, R. Garzon, C. Sevignani, L. Rassenti, H. Alder, S. Volinia, C.G. Liu, T.J. Kipps, M. Negrini, C.M. Croce, A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia, N Engl J Med, 353 (2005) 1793-1801.
[13] L. Ma, J. Teruya-Feldstein, R.A. Weinberg, Tumour invasion and metastasis initiated by microRNA-10b in breast cancer, Nature, 449 (2007) 682-688.
[14] M.L. Si, S. Zhu, H. Wu, Z. Lu, F. Wu, Y.Y. Mo, miR-21-mediated tumor growth, Oncogene, 26 (2007) 2799-2803.
[15] M.V. Iorio, M. Ferracin, C.G. Liu, A. Veronese, R. Spizzo, S. Sabbioni, E. Magri, M. Pedriali, M. Fabbri, M. Campiglio, S. Menard, J.P. Palazzo, A. Rosenberg, P. Musiani, S. Volinia, I. Nenci, G.A. Calin, P. Querzoli, M. Negrini, C.M. Croce, MicroRNA gene expression deregulation in human breast cancer, Cancer Res, 65 (2005) 7065-7070.
[16] L.F. Sempere, M. Christensen, A. Silahtaroglu, M. Bak, C.V. Heath, G. Schwartz, W. Wells, S. Kauppinen, C.N. Cole, Altered MicroRNA expression confined to specific epithelial cell subpopulations in breast cancer, Cancer Res, 67 (2007) 11612-11620.
[17] K.A. Cissell, Y. Rahimi, S. Shrestha, E.A. Hunt, S.K. Deo, Bioluminescence-based detection of microRNA, miR21 in breast cancer cells, Anal Chem, 80 (2008) 2319-2325.
[18] L.X. Yan, Q.N. Wu, Y. Zhang, Y.Y. Li, D.Z. Liao, J.H. Hou, J. Fu, M.S. Zeng, J.P. Yun, Q.L. Wu, Y.X. Zeng, J.Y. Shao, Knockdown of miR-21 in human breast cancer cell lines inhibits proliferation, in vitro migration and in vivo tumor growth, Breast Cancer Res, 13 (2011) R2.
[19] J.A. Chan, A.M. Krichevsky, K.S. Kosik, MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells, Cancer Res, 65 (2005) 6029-6033.
[20] S. Xu, P.D. Witmer, S. Lumayag, B. Kovacs, D. Valle, MicroRNA (miRNA) transcriptome of mouse retina and identification of a sensory organ-specific miRNA cluster, J Biol Chem, 282 (2007) 25053-25066.
[21] Z.B. Jin, G. Hirokawa, L. Gui, R. Takahashi, F. Osakada, Y. Hiura, M. Takahashi, O. Yasuhara, N. Iwai, Targeted deletion of miR-182, an abundant retinal microRNA, Mol Vis, 15 (2009) 523-533.
[22] Q. Zhu, W. Sun, K. Okano, Y. Chen, N. Zhang, T. Maeda, K. Palczewski, Sponge transgenic mouse model reveals important roles for the microRNA-183 (miR-183)/96/182 cluster in postmitotic photoreceptors of the retina, J Biol Chem, 286 (2011) 31749-31760.
[23] M.F. Segura, D. Hanniford, S. Menendez, L. Reavie, X. Zou, S. Alvarez-Diaz, J. Zakrzewski, E. Blochin, A. Rose, D. Bogunovic, D. Polsky, J. Wei, P. Lee, I. Belitskaya-Levy, N. Bhardwaj, I. Osman, E. Hernando, Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor, Proc Natl Acad Sci U S A, 106 (2009) 1814-1819.
[24] C. Huynh, M.F. Segura, A. Gaziel-Sovran, S. Menendez, F. Darvishian, L. Chiriboga, B. Levin, D. Meruelo, I. Osman, J. Zavadil, E.G. Marcusson, E. Hernando, Efficient in vivo microRNA targeting of liver metastasis, Oncogene, 30 (2011) 1481-1488.
[25] L. Jiang, P. Mao, L. Song, J. Wu, J. Huang, C. Lin, J. Yuan, L. Qu, S.Y. Cheng, J. Li, miR-182 as a prognostic marker for glioma progression and patient survival, Am J Pathol, 177 (2010) 29-38.
[26] B.L. Mihelich, E.A. Khramtsova, N. Arva, A. Vaishnav, D.N. Johnson, A.A. Giangreco, E. Martens-Uzunova, O. Bagasra, A. Kajdacsy-Balla, L. Nonn, miR-183-96-182 cluster is overexpressed in prostate tissue and regulates zinc homeostasis in prostate cells, J Biol Chem, 286 (2011) 44503-44511.
[27] Z. Liu, J. Liu, M.F. Segura, C. Shao, P. Lee, Y. Gong, E. Hernando, J.J. Wei, MiR-182 overexpression in tumourigenesis of high-grade serous ovarian carcinoma, J Pathol, 228 (2012) 204-215.
[28] S.D. Weeraratne, V. Amani, N. Teider, J. Pierre-Francois, D. Winter, M.J. Kye, S. Sengupta, T. Archer, M. Remke, A.H. Bai, P. Warren, S.M. Pfister, J.A. Steen, S.L. Pomeroy, Y.J. Cho, Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma, Acta Neuropathol, 123 (2012) 539-552.
[29] J. Wang, J. Li, J. Shen, C. Wang, L. Yang, X. Zhang, MicroRNA-182 downregulates metastasis suppressor 1 and contributes to metastasis of hepatocellular carcinoma, BMC Cancer, 12 (2012) 227.
[30] L. Cekaite, J.K. Rantala, J. Bruun, M. Guriby, T.H. Agesen, S.A. Danielsen, G.E. Lind, A. Nesbakken, O. Kallioniemi, R.A. Lothe, R.I. Skotheim, MiR-9, -31, and -182 deregulation promote proliferation and tumor cell survival in colon cancer, Neoplasia, 14 (2012) 868-879.
[31] K. Tsuchiyama, H. Ito, M. Taga, S. Naganuma, Y. Oshinoya, K.I. Nagano, O. Yokoyama, H. Itoh, Expression of MicroRNAs associated with Gleason grading system in prostate cancer: miR-182-5p is a useful marker for high grade prostate cancer, Prostate, (2012).
[32] Y.Q. Wang, R.D. Guo, R.M. Guo, W. Sheng, L.R. Yin, MicroRNA-182 promotes cell growth, invasion and chemoresistance by targeting programmed cell death 4 (PDCD4) in human ovarian carcinomas, J Cell Biochem, (2013).
[33] T. Tang, H.K. Wong, W. Gu, M.Y. Yu, K.F. To, C.C. Wang, Y.F. Wong, T.H. Cheung, T.K. Chung, K.W. Choy, MicroRNA-182 plays an onco-miRNA role in cervical cancer, Gynecol Oncol, (2013).
[34] H. Liu, L. Du, Z. Wen, Y. Yang, J. Li, L. Wang, X. Zhang, Y. Liu, Z. Dong, W. Li, G. Zheng, C. Wang, Up-regulation of miR-182 expression in colorectal cancer tissues and its prognostic value, Int J Colorectal Dis, (2013).
[35] I.K. Guttilla, B.A. White, Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells, J Biol Chem, 284 (2009) 23204-23216.
[36] B.N. Hannafon, P. Sebastiani, A. de las Morenas, J. Lu, C.L. Rosenberg, Expression of microRNA and their gene targets are dysregulated in preinvasive breast cancer, Breast Cancer Res, 13 (2011) R24.
[37] O. Giricz, P.A. Reynolds, A. Ramnauth, C. Liu, T. Wang, L. Stead, G. Childs, T. Rohan, N. Shapiro, S. Fineberg, P.A. Kenny, O. Loudig, Hsa-miR-375 is differentially expressed during breast lobular neoplasia and promotes loss of mammary acinar polarity, J Pathol, 226 (2012) 108-119.
[38] P. Moskwa, F.M. Buffa, Y. Pan, R. Panchakshari, P. Gottipati, R.J. Muschel, J. Beech, R. Kulshrestha, K. Abdelmohsen, D.M. Weinstock, M. Gorospe, A.L. Harris, T. Helleday, D. Chowdhury, miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors, Mol Cell, 41 (2011) 210-220.
[39] K. Krishnan, A.L. Steptoe, H.C. Martin, S. Wani, K. Nones, N. Waddell, M. Mariasegaram, P.T. Simpson, S.R. Lakhani, B. Gabrielli, A. Vlassov, N. Cloonan, S.M. Grimmond, MicroRNA-182-5p targets a network of genes involved in DNA repair, RNA, (2012).
[40] R. Lei, J. Tang, X. Zhuang, R. Deng, G. Li, J. Yu, Y. Liang, J. Xiao, H.Y. Wang, Q. Yang, G. Hu, Suppression of MIM by microRNA-182 activates RhoA and promotes breast cancer metastasis, Oncogene, (2013).
[41] K.M. Cadigan, R. Nusse, Wnt signaling: a common theme in animal development, Genes Dev, 11 (1997) 3286-3305.
[42] T. Reya, A.W. Duncan, L. Ailles, J. Domen, D.C. Scherer, K. Willert, L. Hintz, R. Nusse, I.L. Weissman, A role for Wnt signalling in self-renewal of haematopoietic stem cells, Nature, 423 (2003) 409-414.
[43] K. Willert, J.D. Brown, E. Danenberg, A.W. Duncan, I.L. Weissman, T. Reya, J.R. Yates, 3rd, R. Nusse, Wnt proteins are lipid-modified and can act as stem cell growth factors, Nature, 423 (2003) 448-452.
[44] L.R. Howe, A.M. Brown, Wnt signaling and breast cancer, Cancer Biol Ther, 3 (2004) 36-41.
[45] T. Reya, H. Clevers, Wnt signalling in stem cells and cancer, Nature, 434 (2005) 843-850.
[46] A.M. Brown, Wnt signaling in breast cancer: have we come full circle?, Breast Cancer Res, 3 (2001) 351-355.
[47] A. Klaus, W. Birchmeier, Wnt signalling and its impact on development and cancer, Nat Rev Cancer, 8 (2008) 387-398.
[48] A. Incassati, A. Chandramouli, R. Eelkema, P. Cowin, Key signaling nodes in mammary gland development and cancer: beta-catenin, Breast Cancer Res, 12 (2010) 213.
[49] R.H. Giles, J.H. van Es, H. Clevers, Caught up in a Wnt storm: Wnt signaling in cancer, Biochim Biophys Acta, 1653 (2003) 1-24.
[50] P. Polakis, Wnt signaling and cancer, Genes Dev, 14 (2000) 1837-1851.
[51] A. Ryo, M. Nakamura, G. Wulf, Y.C. Liou, K.P. Lu, Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC, Nat Cell Biol, 3 (2001) 793-801.
[52] S.Y. Lin, W. Xia, J.C. Wang, K.Y. Kwong, B. Spohn, Y. Wen, R.G. Pestell, M.C. Hung, Beta-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression, Proc Natl Acad Sci U S A, 97 (2000) 4262-4266.
[53] O. Tetsu, F. McCormick, Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells, Nature, 398 (1999) 422-426.
[54] S. Candidus, P. Bischoff, K.F. Becker, H. Hofler, No evidence for mutations in the alpha- and beta-catenin genes in human gastric and breast carcinomas, Cancer Res, 56 (1996) 49-52.
[55] P.W. Schlosshauer, S.A. Brown, K. Eisinger, Q. Yan, E.R. Guglielminetti, R. Parsons, L.H. Ellenson, J. Kitajewski, APC truncation and increased beta-catenin levels in a human breast cancer cell line, Carcinogenesis, 21 (2000) 1453-1456.
[56] F. Ugolini, E. Charafe-Jauffret, V.J. Bardou, J. Geneix, J. Adelaide, F. Labat-Moleur, F. Penault-Llorca, M. Longy, J. Jacquemier, D. Birnbaum, M.J. Pebusque, WNT pathway and mammary carcinogenesis: loss of expression of candidate tumor suppressor gene SFRP1 in most invasive carcinomas except of the medullary type, Oncogene, 20 (2001) 5810-5817.
[57] L. Ai, Q. Tao, S. Zhong, C.R. Fields, W.J. Kim, M.W. Lee, Y. Cui, K.D. Brown, K.D. Robertson, Inactivation of Wnt inhibitory factor-1 (WIF1) expression by epigenetic silencing is a common event in breast cancer, Carcinogenesis, 27 (2006) 1341-1348.
[58] J. Veeck, P.J. Wild, T. Fuchs, P.J. Schuffler, A. Hartmann, R. Knuchel, E. Dahl, Prognostic relevance of Wnt-inhibitory factor-1 (WIF1) and Dickkopf-3 (DKK3) promoter methylation in human breast cancer, BMC Cancer, 9 (2009) 217.
[59] E.L. Huguet, J.A. McMahon, A.P. McMahon, R. Bicknell, A.L. Harris, Differential expression of human Wnt genes 2, 3, 4, and 7B in human breast cell lines and normal and disease states of human breast tissue, Cancer Res, 54 (1994) 2615-2621.
[60] T.D. Bui, J. Rankin, K. Smith, E.L. Huguet, S. Ruben, T. Strachan, A.L. Harris, S. Lindsay, A novel human Wnt gene, WNT10B, maps to 12q13 and is expressed in human breast carcinomas, Oncogene, 14 (1997) 1249-1253.
[61] C.C. Liu, J. Prior, D. Piwnica-Worms, G. Bu, LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy, Proc Natl Acad Sci U S A, 107 (2010) 5136-5141.
[62] G.M. Wulf, A. Ryo, G.G. Wulf, S.W. Lee, T. Niu, V. Petkova, K.P. Lu, Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1, EMBO J, 20 (2001) 3459-3472.
[63] S. Persad, A.A. Troussard, T.R. McPhee, D.J. Mulholland, S. Dedhar, Tumor suppressor PTEN inhibits nuclear accumulation of beta-catenin and T cell/lymphoid enhancer factor 1-mediated transcriptional activation, J Cell Biol, 153 (2001) 1161-1174.
[64] E. Sadot, B. Geiger, M. Oren, A. Ben-Ze'ev, Down-regulation of beta-catenin by activated p53, Mol Cell Biol, 21 (2001) 6768-6781.
[65] C. Takahashi, Z. Sheng, T.P. Horan, H. Kitayama, M. Maki, K. Hitomi, Y. Kitaura, S. Takai, R.M. Sasahara, A. Horimoto, Y. Ikawa, B.J. Ratzkin, T. Arakawa, M. Noda, Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK, Proc Natl Acad Sci U S A, 95 (1998) 13221-13226.
[66] M. Noda, J. Oh, R. Takahashi, S. Kondo, H. Kitayama, C. Takahashi, RECK: a novel suppressor of malignancy linking oncogenic signaling to extracellular matrix remodeling, Cancer Metastasis Rev, 22 (2003) 167-175.
[67] K. Furumoto, S. Arii, A. Mori, H. Furuyama, M.J. Gorrin Rivas, T. Nakao, N. Isobe, T. Murata, C. Takahashi, M. Noda, M. Imamura, RECK gene expression in hepatocellular carcinoma: correlation with invasion-related clinicopathological factors and its clinical significance. Reverse-inducing--cysteine-rich protein with Kazal motifs, Hepatology, 33 (2001) 189-195.
[68] T. Masui, R. Doi, T. Koshiba, K. Fujimoto, S. Tsuji, S. Nakajima, M. Koizumi, E. Toyoda, S. Tulachan, D. Ito, K. Kami, T. Mori, M. Wada, M. Noda, M. Imamura, RECK expression in pancreatic cancer: its correlation with lower invasiveness and better prognosis, Clin Cancer Res, 9 (2003) 1779-1784.
[69] P.N. Span, C.G. Sweep, P. Manders, L.V. Beex, D. Leppert, R.L. Lindberg, Matrix metalloproteinase inhibitor reversion-inducing cysteine-rich protein with Kazal motifs: a prognostic marker for good clinical outcome in human breast carcinoma, Cancer, 97 (2003) 2710-2715.
[70] K. Takenaka, S. Ishikawa, K. Yanagihara, R. Miyahara, S. Hasegawa, Y. Otake, Y. Morioka, C. Takahashi, M. Noda, H. Ito, H. Wada, F. Tanaka, Prognostic significance of reversion-inducing cysteine-rich protein with Kazal motifs expression in resected pathologic stage IIIA N2 non-small-cell lung cancer, Ann Surg Oncol, 12 (2005) 817-824.
[71] T. Takeuchi, M. Hisanaga, M. Nagao, N. Ikeda, H. Fujii, F. Koyama, T. Mukogawa, H. Matsumoto, S. Kondo, C. Takahashi, M. Noda, Y. Nakajima, The membrane-anchored matrix metalloproteinase (MMP) regulator RECK in combination with MMP-9 serves as an informative prognostic indicator for colorectal cancer, Clin Cancer Res, 10 (2004) 5572-5579.
[72] A. Rabien, M. Burkhardt, M. Jung, F. Fritzsche, M. Ringsdorf, H. Schicktanz, S.A. Loening, G. Kristiansen, K. Jung, Decreased RECK expression indicating proteolytic imbalance in prostate cancer is associated with higher tumor aggressiveness and risk of prostate-specific antigen relapse after radical prostatectomy, Eur Urol, 51 (2007) 1259-1266.
[73] J. Oh, R. Takahashi, S. Kondo, A. Mizoguchi, E. Adachi, R.M. Sasahara, S. Nishimura, Y. Imamura, H. Kitayama, D.B. Alexander, C. Ide, T.P. Horan, T. Arakawa, H. Yoshida, S. Nishikawa, Y. Itoh, M. Seiki, S. Itohara, C. Takahashi, M. Noda, The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis, Cell, 107 (2001) 789-800.
[74] N. Meng, Y. Li, H. Zhang, X.F. Sun, RECK, a novel matrix metalloproteinase regulator, Histol Histopathol, 23 (2008) 1003-1010.
[75] L.T. Liu, J.P. Peng, H.C. Chang, W.C. Hung, RECK is a target of Epstein-Barr virus latent membrane protein 1, Oncogene, 22 (2003) 8263-8270.
[76] L.T. Liu, H.C. Chang, L.C. Chiang, W.C. Hung, Induction of RECK by nonsteroidal anti-inflammatory drugs in lung cancer cells, Oncogene, 21 (2002) 8347-8350.
[77] R.M. Sasahara, C. Takahashi, M. Noda, Involvement of the Sp1 site in ras-mediated downregulation of the RECK metastasis suppressor gene, Biochem Biophys Res Commun, 264 (1999) 668-675.
[78] R.M. Sasahara, S.M. Brochado, C. Takahashi, J. Oh, S.S. Maria-Engler, J.M. Granjeiro, M. Noda, M.C. Sogayar, Transcriptional control of the RECK metastasis/angiogenesis suppressor gene, Cancer Detect Prev, 26 (2002) 435-443.
[79] H.C. Chang, L.T. Liu, W.C. Hung, Involvement of histone deacetylation in ras-induced down-regulation of the metastasis suppressor RECK, Cell Signal, 16 (2004) 675-679.
[80] L.T. Liu, H.C. Chang, L.C. Chiang, W.C. Hung, Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion, Cancer Res, 63 (2003) 3069-3072.
[81] M.C. Hsu, H.C. Chang, W.C. Hung, HER-2/neu represses the metastasis suppressor RECK via ERK and Sp transcription factors to promote cell invasion, J Biol Chem, 281 (2006) 4718-4725.
[82] H.C. Chang, C.Y. Cho, W.C. Hung, Silencing of the metastasis suppressor RECK by RAS oncogene is mediated by DNA methyltransferase 3b-induced promoter methylation, Cancer Res, 66 (2006) 8413-8420.
[83] C.Y. Cho, J.H. Wang, H.C. Chang, C.K. Chang, W.C. Hung, Epigenetic inactivation of the metastasis suppressor RECK enhances invasion of human colon cancer cells, J Cell Physiol, 213 (2007) 65-69.
[84] C.H. Chien, Y.M. Sun, W.C. Chang, P.Y. Chiang-Hsieh, T.Y. Lee, W.C. Tsai, J.T. Horng, A.P. Tsou, H.D. Huang, Identifying transcriptional start sites of human microRNAs based on high-throughput sequencing data, Nucleic Acids Res, 39 (2011) 9345-9356.
[85] A. Gokhale, R. Kunder, A. Goel, R. Sarin, A. Moiyadi, A. Shenoy, C. Mamidipally, S. Noronha, S. Kannan, N.V. Shirsat, Distinctive microRNA signature of medulloblastomas associated with the WNT signaling pathway, J Cancer Res Ther, 6 (2010) 521-529.
[86] S. Handeli, J.A. Simon, A small-molecule inhibitor of Tcf/beta-catenin signaling down-regulates PPARgamma and PPARdelta activities, Mol Cancer Ther, 7 (2008) 521-529.
[87] M. Vaid, R. Prasad, Q. Sun, S.K. Katiyar, Silymarin targets beta-catenin signaling in blocking migration/invasion of human melanoma cells, PLoS One, 6 (2011) e23000.
[88] A.B. Stittrich, C. Haftmann, E. Sgouroudis, A.A. Kuhl, A.N. Hegazy, I. Panse, R. Riedel, M. Flossdorf, J. Dong, F. Fuhrmann, G.A. Heinz, Z. Fang, N. Li, U. Bissels, F. Hatam, A. Jahn, B. Hammoud, M. Matz, F.M. Schulze, R. Baumgrass, A. Bosio, H.J. Mollenkopf, J. Grun, A. Thiel, W. Chen, T. Hofer, C. Loddenkemper, M. Lohning, H.D. Chang, N. Rajewsky, A. Radbruch, M.F. Mashreghi, The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes, Nat Immunol, 11 (2010) 1057-1062.
[89] G. Li, C. Luna, J. Qiu, D.L. Epstein, P. Gonzalez, Alterations in microRNA expression in stress-induced cellular senescence, Mech Ageing Dev, 130 (2009) 731-741.
[90] F.C. Geyer, M. Lacroix-Triki, K. Savage, M. Arnedos, M.B. Lambros, A. MacKay, R. Natrajan, J.S. Reis-Filho, beta-Catenin pathway activation in breast cancer is associated with triple-negative phenotype but not with CTNNB1 mutation, Mod Pathol, 24 (2011) 209-231.
[91] L. Yang, X. Wu, Y. Wang, K. Zhang, J. Wu, Y.C. Yuan, X. Deng, L. Chen, C.C. Kim, S. Lau, G. Somlo, Y. Yen, FZD7 has a critical role in cell proliferation in triple negative breast cancer, Oncogene, 30 (2011) 4437-4446.
[92] T.D. King, M.J. Suto, Y. Li, The Wnt/beta-catenin signaling pathway: a potential therapeutic target in the treatment of triple negative breast cancer, J Cell Biochem, 113 (2012) 13-18.
[93] C.P. Prasad, G. Rath, S. Mathur, D. Bhatnagar, R. Ralhan, Potent growth suppressive activity of curcumin in human breast cancer cells: Modulation of Wnt/beta-catenin signaling, Chem Biol Interact, 181 (2009) 263-271.
[94] H. Liu, Y. Wang, X. Li, Y.J. Zhang, J. Li, Y.Q. Zheng, M. Liu, X. Song, X.R. Li, Expression and regulatory function of miRNA-182 in triple-negative breast cancer cells through its targeting of profilin 1, Tumour Biol, (2013).
[95] Z. Zhang, Z. Li, C. Gao, P. Chen, J. Chen, W. Liu, S. Xiao, H. Lu, miR-21 plays a pivotal role in gastric cancer pathogenesis and progression, Lab Invest, 88 (2008) 1358-1366.
[96] G. Gabriely, T. Wurdinger, S. Kesari, C.C. Esau, J. Burchard, P.S. Linsley, A.M. Krichevsky, MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators, Mol Cell Biol, 28 (2008) 5369-5380.
[97] S.J. Hu, G. Ren, J.L. Liu, Z.A. Zhao, Y.S. Yu, R.W. Su, X.H. Ma, H. Ni, W. Lei, Z.M. Yang, MicroRNA expression and regulation in mouse uterus during embryo implantation, J Biol Chem, 283 (2008) 23473-23484.
[98] F. Loayza-Puch, Y. Yoshida, T. Matsuzaki, C. Takahashi, H. Kitayama, M. Noda, Hypoxia and RAS-signaling pathways converge on, and cooperatively downregulate, the RECK tumor-suppressor protein through microRNAs, Oncogene, 29 (2010) 2638-2648.
[99] H.M. Jung, B.L. Phillips, R.S. Patel, D.M. Cohen, A. Jakymiw, W.W. Kong, J.Q. Cheng, E.K. Chan, Keratinization-associated miR-7 and miR-21 regulate tumor suppressor reversion-inducing cysteine-rich protein with kazal motifs (RECK) in oral cancer, J Biol Chem, 287 (2012) 29261-29272.
[100] S.T. Reis, J. Pontes-Junior, A.A. Antunes, M.F. Dall'Oglio, N. Dip, C.C. Passerotti, G.A. Rossini, D.R. Morais, A.J. Nesrallah, C. Piantino, M. Srougi, K.R. Leite, miR-21 may acts as an oncomir by targeting RECK, a matrix metalloproteinase regulator, in prostate cancer, BMC Urol, 12 (2012) 14.
[101] L. Han, X. Yue, X. Zhou, F.M. Lan, G. You, W. Zhang, K.L. Zhang, C.Z. Zhang, J.Q. Cheng, S.Z. Yu, P.Y. Pu, T. Jiang, C.S. Kang, MicroRNA-21 expression is regulated by beta-catenin/STAT3 pathway and promotes glioma cell invasion by direct targeting RECK, CNS Neurosci Ther, 18 (2012) 573-583.
[102] Y. Yang, R. Chaerkady, M.A. Beer, J.T. Mendell, A. Pandey, Identification of miR-21 targets in breast cancer cells using a quantitative proteomic approach, Proteomics, 9 (2009) 1374-1384.
[103] L.B. Frankel, N.R. Christoffersen, A. Jacobsen, M. Lindow, A. Krogh, A.H. Lund, Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells, J Biol Chem, 283 (2008) 1026-1033.
[104] F. Meng, R. Henson, H. Wehbe-Janek, K. Ghoshal, S.T. Jacob, T. Patel, MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer, Gastroenterology, 133 (2007) 647-658.
[105] H. Hirata, K. Ueno, V. Shahryari, Y. Tanaka, Z.L. Tabatabai, Y. Hinoda, R. Dahiya, Oncogenic miRNA-182-5p targets Smad4 and RECK in human bladder cancer, PLoS One, 7 (2012) e51056.
[106] H. Hirata, K. Ueno, V. Shahryari, G. Deng, Y. Tanaka, Z.L. Tabatabai, Y. Hinoda, R. Dahiya, MicroRNA-182-5p promotes cell invasion and proliferation by down regulating FOXF2, RECK and MTSS1 genes in human prostate cancer, PLoS One, 8 (2013) e55502.
[107] D. Raman, P.J. Baugher, Y.M. Thu, A. Richmond, Role of chemokines in tumor growth, Cancer Lett, 256 (2007) 137-165.
[108] F. Balkwill, Cancer and the chemokine network, Nat Rev Cancer, 4 (2004) 540-550.
[109] S. Ali, G. Lazennec, Chemokines: novel targets for breast cancer metastasis, Cancer Metastasis Rev, 26 (2007) 401-420.
[110] R.M. Ransohoff, Chemokines and chemokine receptors: standing at the crossroads of immunobiology and neurobiology, Immunity, 31 (2009) 711-721.
[111] K. Ley, C. Laudanna, M.I. Cybulsky, S. Nourshargh, Getting to the site of inflammation: the leukocyte adhesion cascade updated, Nat Rev Immunol, 7 (2007) 678-689.
[112] S.J. Youngs, S.A. Ali, D.D. Taub, R.C. Rees, Chemokines induce migrational responses in human breast carcinoma cell lines, Int J Cancer, 71 (1997) 257-266.
[113] A. Muller, B. Homey, H. Soto, N. Ge, D. Catron, M.E. Buchanan, T. McClanahan, E. Murphy, W. Yuan, S.N. Wagner, J.L. Barrera, A. Mohar, E. Verastegui, A. Zlotnik, Involvement of chemokine receptors in breast cancer metastasis, Nature, 410 (2001) 50-56.
[114] T. Murakami, W. Maki, A.R. Cardones, H. Fang, A. Tun Kyi, F.O. Nestle, S.T. Hwang, Expression of CXC chemokine receptor-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells, Cancer Res, 62 (2002) 7328-7334.
[115] M.C. Smith, K.E. Luker, J.R. Garbow, J.L. Prior, E. Jackson, D. Piwnica-Worms, G.D. Luker, CXCR4 regulates growth of both primary and metastatic breast cancer, Cancer Res, 64 (2004) 8604-8612.
[116] K. Xie, Interleukin-8 and human cancer biology, Cytokine Growth Factor Rev, 12 (2001) 375-391.
[117] X. Le, Q. Shi, B. Wang, Q. Xiong, C. Qian, Z. Peng, X.C. Li, H. Tang, J.L. Abbruzzese, K. Xie, Molecular regulation of constitutive expression of interleukin-8 in human pancreatic adenocarcinoma, J Interferon Cytokine Res, 20 (2000) 935-946.
[118] N. Mukaida, S. Okamoto, Y. Ishikawa, K. Matsushima, Molecular mechanism of interleukin-8 gene expression, J Leukoc Biol, 56 (1994) 554-558.
[119] Q. Shi, J.L. Abbruzzese, S. Huang, I.J. Fidler, Q. Xiong, K. Xie, Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic, Clin Cancer Res, 5 (1999) 3711-3721.
[120] C. Hensley, S. Spitzler, B.E. McAlpine, M. Lynn, J.C. Ansel, A.R. Solomon, C.A. Armstrong, In vivo human melanoma cytokine production: inverse correlation of GM-CSF production with tumor depth, Exp Dermatol, 7 (1998) 335-341.
[121] W. Nurnberg, D. Tobias, F. Otto, B.M. Henz, D. Schadendorf, Expression of interleukin-8 detected by in situ hybridization correlates with worse prognosis in primary cutaneous melanoma, J Pathol, 189 (1999) 546-551.
[122] R.K. Singh, M.L. Varney, C.D. Bucana, S.L. Johansson, Expression of interleukin-8 in primary and metastatic malignant melanoma of the skin, Melanoma Res, 9 (1999) 383-387.
[123] M. Gutman, R.K. Singh, K. Xie, C.D. Bucana, I.J. Fidler, Regulation of interleukin-8 expression in human melanoma cells by the organ environment, Cancer Res, 55 (1995) 2470-2475.
[124] S. Huang, J.B. Robinson, A. Deguzman, C.D. Bucana, I.J. Fidler, Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8, Cancer Res, 60 (2000) 5334-5339.
[125] G.F. Greene, Y. Kitadai, C.A. Pettaway, A.C. von Eschenbach, C.D. Bucana, I.J. Fidler, Correlation of metastasis-related gene expression with metastatic potential in human prostate carcinoma cells implanted in nude mice using an in situ messenger RNA hybridization technique, Am J Pathol, 150 (1997) 1571-1582.
[126] S. Wu, H. Shang, L. Cui, Z. Zhang, Y. Zhang, Y. Li, J. Wu, R.K. Li, J. Xie, Targeted blockade of interleukin-8 abrogates its promotion of cervical cancer growth and metastasis, Mol Cell Biochem, 375 (2013) 69-79.
[127] Y.S. Lee, I. Choi, Y. Ning, N.Y. Kim, V. Khatchadourian, D. Yang, H.K. Chung, D. Choi, M.J. LaBonte, R.D. Ladner, K.C. Nagulapalli Venkata, D.O. Rosenberg, N.A. Petasis, H.J. Lenz, Y.K. Hong, Interleukin-8 and its receptor CXCR2 in the tumour microenvironment promote colon cancer growth, progression and metastasis, Br J Cancer, 106 (2012) 1833-1841.
[128] C. Chavey, F. Bibeau, S. Gourgou-Bourgade, S. Burlinchon, F. Boissiere, D. Laune, S. Roques, G. Lazennec, Oestrogen receptor negative breast cancers exhibit high cytokine content, Breast Cancer Res, 9 (2007) R15.
[129] A. Freund, C. Chauveau, J.P. Brouillet, A. Lucas, M. Lacroix, A. Licznar, F. Vignon, G. Lazennec, IL-8 expression and its possible relationship with estrogen-receptor-negative status of breast cancer cells, Oncogene, 22 (2003) 256-265.
[130] A. Freund, V. Jolivel, S. Durand, N. Kersual, D. Chalbos, C. Chavey, F. Vignon, G. Lazennec, Mechanisms underlying differential expression of interleukin-8 in breast cancer cells, Oncogene, 23 (2004) 6105-6114.
[131] M.S. Bendre, D.C. Montague, T. Peery, N.S. Akel, D. Gaddy, L.J. Suva, Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease, Bone, 33 (2003) 28-37.
[132] B. Singh, J.A. Berry, L.E. Vincent, A. Lucci, Involvement of IL-8 in COX-2-mediated bone metastases from breast cancer, J Surg Res, 134 (2006) 44-51.
[133] D.R. Smith, P.J. Polverini, S.L. Kunkel, M.B. Orringer, R.I. Whyte, M.D. Burdick, C.A. Wilke, R.M. Strieter, Inhibition of interleukin 8 attenuates angiogenesis in bronchogenic carcinoma, J Exp Med, 179 (1994) 1409-1415.
[134] R.M. Strieter, P.J. Polverini, D.A. Arenberg, A. Walz, G. Opdenakker, J. Van Damme, S.L. Kunkel, Role of C-X-C chemokines as regulators of angiogenesis in lung cancer, J Leukoc Biol, 57 (1995) 752-762.
[135] J.E. Nor, J. Christensen, D.J. Mooney, P.J. Polverini, Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression, Am J Pathol, 154 (1999) 375-384.
[136] J. Heidemann, H. Ogawa, M.B. Dwinell, P. Rafiee, C. Maaser, H.R. Gockel, M.F. Otterson, D.M. Ota, N. Lugering, W. Domschke, D.G. Binion, Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2, J Biol Chem, 278 (2003) 8508-8515.
[137] J. Li, F. Li, H. Wang, X. Wang, Y. Jiang, D. Li, Wortmannin reduces metastasis and angiogenesis of human breast cancer cells via nuclear factor-kappaB-dependent matrix metalloproteinase-9 and interleukin-8 pathways, J Int Med Res, 40 (2012) 867-876.
[138] K.S. Hill, I. Gaziova, L. Harrigal, Y.A. Guerra, S. Qiu, S.K. Sastry, T. Arumugam, C.D. Logsdon, L.A. Elferink, Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer, PLoS One, 7 (2012) e40420.
[139] M.S. Ebert, J.R. Neilson, P.A. Sharp, MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells, Nat Methods, 4 (2007) 721-726.
[140] C. Scotton, D. Milliken, J. Wilson, S. Raju, F. Balkwill, Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours, Br J Cancer, 85 (2001) 891-897.
[141] A. Sica, A. Saccani, B. Bottazzi, N. Polentarutti, A. Vecchi, J. van Damme, A. Mantovani, Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages, J Immunol, 164 (2000) 762-767.
[142] A. Mantovani, S. Sozzani, M. Locati, P. Allavena, A. Sica, Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes, Trends Immunol, 23 (2002) 549-555.
[143] E.Y. Lin, A.V. Nguyen, R.G. Russell, J.W. Pollard, Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy, J Exp Med, 193 (2001) 727-740.
[144] B. Vicinus, C. Rubie, S.K. Faust, V.O. Frick, P. Ghadjar, M. Wagner, S. Graeber, M.K. Schilling, miR-21 functionally interacts with the 3'UTR of chemokine CCL20 and down-regulates CCL20 expression in miR-21 transfected colorectal cancer cells, Cancer Lett, 316 (2012) 105-112.
[145] C.L. Elliott, V.C. Allport, J.A. Loudon, G.D. Wu, P.R. Bennett, Nuclear factor-kappa B is essential for up-regulation of interleukin-8 expression in human amnion and cervical epithelial cells, Mol Hum Reprod, 7 (2001) 787-790.