JCT  Vol.6 No.7 , July 2015
Progress in Competing Endogenous RNA and Cancer
Author(s) Ting Zhang1, Weiguo Huang1,2*
ABSTRACT
The competing endogenous RNA (ceRNA) hypothesis was introduced as a previously unrecognized gene regulatory layer. This is a recently discovered hypothesis about how mRNAs, pseudogene transcripts, long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) regulate post-transcriptional expression by sharing common microRNA response elements (MREs) to compete for the binding of microRNAs (miRNAs) and inhibiting normal miRNA targeting activity on mRNA. Previous study have found that ceRNAs are key regulators in many biological processes such as cell cycle, tumor initiation and progression and found to be involved in several diseases, especially in tumor. Tumor is a kind of serious disease with high death rate. Recently, there is no effective therapy for Tumor. The mechanism of many tumors has not yet been fully elucidated. It has been proved that a number of ceRNAs identified as aberrantly expressed during tumor development. It is vital to understand how ceRNA works in tumor progression and to find a new way to cure those corresponding disease. This review introduces the mechanism of ceRNA hypothesis, focus on the history of the ceRNA hypothesis, the important pathophysiological roles of ceRNAs in tumor and the latest findings about how ceRNA works in gastric cancer, lung cancer, endometrial cancer, breast cancer, liver cancer, colorectal cancer and melanoma.

Cite this paper
Zhang, T. , Huang, W. (2015) Progress in Competing Endogenous RNA and Cancer. Journal of Cancer Therapy, 6, 622-630. doi: 10.4236/jct.2015.67068.
References
[1]   Salmena, L., Poliseno, L., Tay, Y., Kats, L. and Pandolfi, P.P. (2011) A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language? Cell, 146, 353-358.
http://dx.doi.org/10.1016/j.cell.2011.07.014

[2]   Bartel, D.P. (2004) MicroRNAs: Genomics, Biogenesis, Mechanism, and Function. Cell, 116, 281-297.
http://dx.doi.org/10.1016/S0092-8674(04)00045-5

[3]   Bartel, D.P. (2009) MicroRNAs: Target Recognition and Regulatory Functions. Cell, 136, 215-233.
http://dx.doi.org/10.1016/j.cell.2009.01.002

[4]   Chekulaeva, M. and Filipowicz, W. (2009) Mechanisms of miRNA Mediated Post-Transcriptional Regulation in Animal Cells. Current Opinion in Cell Biology, 21, 452-460.
http://dx.doi.org/10.1016/j.ceb.2009.04.009

[5]   Friedman, R.C., Farh, K.K., Burge, C.B. and Bartel, D.P. (2009) Most Mammalian mRNAs Are Conserved Targets of microRNAs. Genome Research, 19, 92-105.
http://dx.doi.org/10.1101/gr.082701.108

[6]   Poliseno, L., Salmena, L., Zhang, J., Carver, B., Haveman, W.J. and Pandilfi, P.P. (2010) A Coding-Independent Function of Gene and Pseudogene mRNAs Regulates Tumour Biology. Nature, 465, 1033-1038.
http://dx.doi.org/10.1038/nature09144

[7]   Cesana, M., Cacchiarelli, D., Leqnini, I., Santini, T., Sthandier, O., Chinappi, M., Tramontano, A. and Bozzoni, I. (2011) A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNA. Cell, 147, 358-369.
http://dx.doi.org/10.1016/j.cell.2011.09.028

[8]   Ebert, M.S. and Sharp, P.A. (2010) MicroRNA Sponges: Progress and Possibilities. RNA, 16, 2043-2050.
http://dx.doi.org/10.1261/rna.2414110

[9]   Tay, Y., Kats, L., Salmena, L., Weiss, D., Tan, S.M., Ala, U., Karreth, F., Poliseno, L., Provero, P., Di Cunto, F., Lieberman, J., Riqoutsos, I. and Pandolfi, P.P. (2011) Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous mRNAs. Cell, 147, 344-357.
http://dx.doi.org/10.1016/j.cell.2011.09.029

[10]   Sumazin, P., Yang, X., Chiu, H.S., Chung, W.J., Iyer, A., Llobet-Navas, D., Raibhandari, P., Bansal, M., Guarnieri, P., Silva, J. and Califano, A. (2011) An Extensive microRNA-Mediated Network of RNA-RNA Interactions Regulates Established Oncogenic Pathways in Glioblastoma. Cell, 147, 370-381.
http://dx.doi.org/10.1016/j.cell.2011.09.041

[11]   Karreth, F.A., Tay, Y., Perna, D., Ala, U., Tan, S.M., Rust, A.G., DeNicola, G., Webster, K.A., Weiss, D., Perez-Mancera, P.A., Krauthammer, M., Halaban, R., Proero, P., Adams, D.J., Tuveson, D.A. and Pandolfi, P.P. (2011) In Vivo Identification of Tumor-Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma. Cell, 147, 382-395.
http://dx.doi.org/10.1016/j.cell.2011.09.032

[12]   Cesana, M., Cacchiarelli, D., Leqnini, I., Santini, T., Sthandier, O., Chinappi, M., Tramontano, A. and Bozzoni, I. (2011) A long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNA. Cell, 147, 358-369.
http://dx.doi.org/10.1016/j.cell.2011.09.028

[13]   Ebert, M.S., Neilson, J.R. and Sharp, P.A. (2007) microRNA Sponges: Competitive Inhibitors of Small RNAs in Mammalian Cells. Nature Methods, 4, 721-726.
http://dx.doi.org/10.1038/nmeth1079

[14]   Seitz, H. (2009) Redefining microRNA Targets. Current Biology, 19, 870-873.
http://dx.doi.org/10.1016/j.cub.2009.03.059

[15]   Arvey, A., Larsson, E., Sander, C., Leslie, C.S. and Marks, D.S. (2010) Target mRNA Abundance Dilutes microRNA and siRNA Activity. Molecular Systems Biology, 6, 363.

[16]   Ebert, M.S. and Sharp, P.A. (2010) Emerging Roles for Natural microRNA Sponges. Current Biology, 20, R858-R861.
http://dx.doi.org/10.1016/j.cub.2010.08.052

[17]   Franco-Zorrilla, J.M., Valli, A., Todesco, M., Mateos, I., Puga, M.I., Rubio-somozal, I., Levva, A., Weiqel, D., Garcia, J.A. and Paz-Ares, J. (2007) Target Mimicry Provides a New Mechanism for Regulation of microRNA Activity. Nature Genetics, 39, 1033-1037.
http://dx.doi.org/10.1038/ng2079

[18]   Cazalla, D., Yario, T. and Steitz, J.A. (2010) Down-Regulation of a Host microRNA by a Herpesvirus saimiri Noncoding RNA. Science, 328, 1563-1566.
http://dx.doi.org/10.1126/science.1187197

[19]   Ala, U., Karreth, F.A., Bosia, C., Pagnani, A., Taulli, R., Leopold, V., Tay, Y., Provero, P., Zechina, R. and Pandolfi, P.P. (2013) Integrated Transcriptional and Competitive Endogenous RNA Networks Are Cross-Regulated in Permissive Molecular Environments. Proceedings of the National Academy of Sciences of the United States of America, 110, 7154-7159.
http://dx.doi.org/10.1073/pnas.1222509110

[20]   Cesana, M. and Daley, G.Q. (2013) Deciphering the Rules of ceRNA Networks. Proceedings of the National Academy of Sciences of the United States of America, 110, 7112-7113.
http://dx.doi.org/10.1073/pnas.1305322110

[21]   Coburn, N.G. (2009) Lymph Nodes and Gastric Cancer. Journal of Surgical Oncology, 99, 199-206.
http://dx.doi.org/10.1002/jso.21224

[22]   Shi, Y. and Zhou, Y. (2010) The Role of Surgery in the Treatment of Gastric Cancer. Journal of Surgical Oncology, 101, 687-692.

[23]   Lee, H.E., Park, K.U., Yoo, S.B., Nam, S.K., Park, D, J., Kim, H.H. and Lee, H.S. (2013) Clinical Significance of Intratumoral HER2 Heterogeneity in Gastric Cancer. European Journal of Cancer, 49, 1448-1457.
http://dx.doi.org/10.1016/j.ejca.2012.10.018

[24]   Rinn, J.L., Kertesz, M., Wang, J.K., Squazzo, S.L., Xu, X., Bruqmann, S.A., Goodnough, L.H., Helms, J.A., Farnham, P.J., Seqal, E. and Chang, H.Y. (2007) Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs. Cell, 129, 1311-1323.
http://dx.doi.org/10.1016/j.cell.2007.05.022

[25]   Liu, X.H., Sun, M., Nie, F.Q., Ge, Y.B., Zhang, E.B., Yin, D.D., Kong, R., Xia, R., Lu, K.H., Li, J.H., De, W., Wang, K.M. and Wang, Z.X. (2014) Lnc RNA HOTAIR Functions as a Competing Endogenous RNA to Regulate HER2 Expression by Sponging miR-331-3p in Gastric Cancer. Molecular Cancer, 13, 92.

[26]   Kumar, M.S., Armenteros-Monterroso, E., Eat, P., Chakravorty, P., Matthews, N., Winslow, M.M. and Downward, J. (2014) HMGA2 Functions as a Competing Endogenous RNA to Promote Lung Cancer Progression. Nature, 505, 212-217.
http://dx.doi.org/10.1038/nature12785

[27]   Mayr, C., Hemann, M.T. and Bartel, D.P. (2007) Disrupting the Pairing between Let-7 and Hmga2 Enhances Oncogenic Transformation. Science, 315, 1576-1579.
http://dx.doi.org/10.1126/science.1137999

[28]   Kumar, M.S., Erkeland, S.J., Pester, R.E., Chen, C.Y., Ebert, M.S., Sharp, P.A. and Jacks, T. (2008) Suppression of Non-Small Cell Lung Tumor Development by the Let-7 microRNA Family. Proceedings of the National Academy of Sciences of the United States of America, 105, 3903-3908.
http://dx.doi.org/10.1073/pnas.0712321105

[29]   Zhou, X., Zhou, Y.P., Huang, G.R., Gong, B.L., Yang, B., Zhang, D.X., Hu, P. and Xu, S.R. (2011) Expression of the Stem Cell Marker, Nanog, in Human Endometrial Adenocarcinoma. International Journal of Gynecological Pathology, 30, 262-270.
http://dx.doi.org/10.1097/PGP.0b013e3182055a1f

[30]   Wu, Y., Liu, S., Xin, H., Jiang, J., Younglay, E., Sun, S. and Wang, H. (2011) Up-Regulation of microRNA-145 Promotes Differentiation by Repressing OCT4 in Human Endemetrial Adenocarcinoma Cells. Cancer, 117, 3989-3998.
http://dx.doi.org/10.1002/cncr.25944

[31]   Zhou, X., Gao, Q., Wang, J., Zhang, X., Liu, K. and Duan, Z. (2014) Linc-RNA-RoR Acts as a “Sponge” against Mediation of the Differentiation of Endometrial Cancer Stem Cells by microRNA-145. Gynecologic Oncology, 133, 333-339.
http://dx.doi.org/10.1016/j.ygyno.2014.02.033

[32]   Ulitsky, I. and Bartel, D.P. (2013) LincRNAs: Genomics, Evolution, and Mechanisms. Cell, 154, 26-46.
http://dx.doi.org/10.1016/j.cell.2013.06.020

[33]   Wang, Y., Xu, Z., Jiang, J., Xu, C., Kang, J., Xiao, L., Wu, M., Xiong, J., Guo, X. and Liu, H. (2013) Endogenous miRNA Sponge lincRNA-RoR Regulates Oct4, Nanog, and Sox2 in Human Embryonic Stem Cell Self-Renewal. Developmental Cell, 25, 69-80.
http://dx.doi.org/10.1016/j.devcel.2013.03.002

[34]   Loewer, S., Cabili, M.N., Guttman, M., Loh, Y.H., Thomas, K., Park, I.H., Garber, M., Curran, M., Onder, T., Agarwal, S., Manos, P.D., DAtta, S., Lander, E.S., Schlaeger, T.M., Daley, G.Q. and Rinn, J.L. (2010) Large Intergenic Non-Coding RNA-RoR Modulates Reprogramming of Human Induced Pluripotent Stem Cells. Nature Genetics, 42, 1113-1117.
http://dx.doi.org/10.1038/ng.710

[35]   Fang, L., Dum, W.W., Yang, X., Chen, K., Ghanekar, A., Levy, G., Yang, W., Yee, A.J., Lu, W.Y., Xuan, J.W., Gao, Z., Xie, F., He, C., Deng, Z. and Yang, B.B. (2013) Versican 3’-Untranslated Region (3’-UTR) Functions as a ceRNA in Inducing the Development of Hepatocellular Carcinoma by Regulating miRNA Activity. The Journal of the Federation of American Societies for Experimental Biology, 27, 907-919.
http://dx.doi.org/10.1096/fj.12-220905

[36]   Lee, D.Y., Jeyapalan, Z., Fang, L., Yang, J., Yee, A.Y., Li, M., Du, W.W., Shatseva, T. and Yang, B.B. (2010) Expression of Versican 3’-Untranslated Region Modulates Endogenous microRNA Functions. PLoS ONE, 5, e13599.

[37]   Jeyapalan, Z., Deng, Z., Shatseva, Z., Fang, L., He, C. and Yang, B.B. (2011) Expression of CD44 3’-Untranslated Region Regulates Endogenous microRNA Functions in Tumorigenesis and Angiogenesis. Nucleic Acids Research, 39, 3026-3041.
http://dx.doi.org/10.1093/nar/gkq1003

[38]   Yang, J., Li, T., Gao, C., Lv, X., Liu, K., Song, H., Xing, Y. and Xi, T. (2014) FOXO1 3’UTR Functions as a ceRNA in Repressing the Metastases of Breast Cancer Cells via Regulating miRNA Activity. Federation of European Biochemical Societies, 588, 3218-3224.
http://dx.doi.org/10.1016/j.febslet.2014.07.003

[39]   Ma, L., Young, J., Prabhala, H., Pan, E., Mestdagh, P., Muth, D., Teruya-Feldstein, J., Reinhardt, F., Onder, T.T., Valastyan, S., Westermann, F., Vandesompele, J. and Weinberg, R.A. (2010) MiR-9, a MYC/MYCN-Activated microRNA, Regulates E-Cadherin and Cancer Metastasis. Nature Cell Biology, 12, 247-56.

[40]   Ala, U., Karreth, F.A., Bosia, C., Pagnani, A., Taulli, R., Leopold, V., Tay, Y., Provero, P., Zecchina, R. and Pandolfi, P.P. (2013) Integrated Transcriptional and Competitive Endogenous RNA Networks Are Cross-Regulated in Permissive Molecular Environment. Proceedings of the National Academy of Sciences of the United States of America, 10, 7154-7159.
http://dx.doi.org/10.1073/pnas.1222509110

[41]   Wang, J., Liu, X., Wu, H., Ni, P., Gu, Z., Qiao, Y., Chen, N., Sun, F. and Fan, Q. (2010) CREB Up-Regulates Long Non-Coding RNA, HULC Expression through Interaction with microRNA-372 in Liver Cancer. Nucleic Acids Research, 38, 5366-5383.
http://dx.doi.org/10.1093/nar/gkq285

[42]   Yin, X., Li, Y.W., Zhang, B.H., Ren, Z.G., Qiu, S.J., Yi, Y. and Fan, J. (2012) Coexpression of Stemness Factors Oct4 and Nanog Predict Liver Resection. Annals of Surgical Oncology, 19, 2877-2887.

[43]   Qian, Y.W., Chen, Y., Yang, W., Fu, J., Cao, J., Ren, Y.B., Zhu, J.J., Su, B., Luo, T., Zhao, X.F., Dai, R.Y., Li, J.J., Sun, W., Wu, M.C., Feng, G.S. and Wang, H.Y. (2012) p28(GANK) Prevents Degradation of Oct4 and Promotes Expansion of Tumor-Initiating Cells in Hepatocarcinogenesis. Gastroenterology, 142, 1547-1558.
http://dx.doi.org/10.1053/j.gastro.2012.02.042

[44]   Atlasi, Y., Mowla, S.J., Ziaee, S.A. and Bahrami, A.R. (2007) OCT-4, an Embryonic Stem Cell Marker, Is Highly Expressed in Bladder Cancer. International Journal of Cancer, 120, 1598-1602.

[45]   Cheng, L., Sung, M.T., Cossu-Rocca, P., Jones, T.D., Maclennan, G.T., De Jong, J., Lopez-Beltran, A., Montironi, R. and Looijenga, L.H. (2007) OCT4: Biological Functions and Clinical Applications as a Marker of Germ Cell Neoplasia. The Journal of pathology, 211, 1-9.

[46]   Wang, L., Guo, Z.Y., Zhang, R., Xin, B., Chen, R., Zhao, J., Wang, T., Wen, W.H., Jia, L.T., Yao, L.B. and Yang, A.G. (2013) Pseudogene OCT4-pg4 Functions as a Natural Micro RNA Sponge to Regulate OCT4 Expression by Competing for miR-145 in Hepatocellular Carcinoma. Carcinogenesis, 34, 1773-1781.
http://dx.doi.org/10.1093/carcin/bgt139

[47]   Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E. and Forman, D. (2011) Global Cancer Statistics. CA: A Cancer Journal for Clinicians, 61, 69-90.
http://dx.doi.org/10.3322/caac.20107

[48]   Sundaram, P., Hultine, S., Smith, L.M., Dews, M., Fox, J.L., Biyashev, D., Schelter, J.M., Huang, Q., Clear, M.A., Volpert, O.V. and Thomas-Tikhonenko, A. (2011) p53-Responsive miR-194 Inhibits Thrombospondin-1 and Promotes Angiogenesis in Colon Cancers. Cancer Research, 71, 7490-7501.
http://dx.doi.org/10.1158/0008-5472.CAN-11-1124

[49]   Okamoto, K., Ishiguro, T., Midorikawa, Y., Ohata, H., Izumiya, M., Tsuchiya, N., Sato, A., Sakai, H. and Nakagama, H. (2012) miR-493 Induction during Carcinogenesis Blocks Metastatic Settlement of Colon Cancer Cells in Liver. The EMBO Journal, 31, 1752-1763.
http://dx.doi.org/10.1038/emboj.2012.25

[50]   Luo, H., Zou, J., Dong, Z., Zeng, Q., Wu, D. and Liu, L. (2012) Up-Regulated miR-17 Promotes Cell Proliferation, Tumour Growth and Cell Cycle Progression by Targeting the RND3 Tumour Suppressor Gene in Colorectal Carcinoma. Biochemical Journal, 442, 311-321.
http://dx.doi.org/10.1042/BJ20111517

[51]   Almeida, M.I., Nicoloso, M.S., Zeng, L., Ivan, C., Spizzo, R., Gafa, R., Xiao, L., Zhang, X., Vannini, I., Fanini, F., Fabbri, M., Lanza, G., Reis, R.M., Zweidler-Mckay, P.A. and Calin, G.A. (2012) Strand-Specific miR-28-5p and miR-28-3p Have Distinct Effects in Colorectal Cancer Cells. Gastroenterology, 142, 886-896.
http://dx.doi.org/10.1053/j.gastro.2011.12.047

 
 
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