Abstract
miRNAs are a class of non-coding RNAs that play fundamental roles through the post-transcriptional regulation of target mRNAs. miRNAs have been shown to regulate a broad spectrum of biological activities, including development, differentiation, cell death, and oncogenesis. However, little is known about their contribution to cellular senescence. The authors analyzed the expression of 576 miRNAs in proliferating and senescent normal human fibroblasts by microarray, and identified 12 miRNAs that were differentially expressed in proliferating and senescent fibroblasts. Interestingly, all six miRNAs that were down-regulated in senescent cells had been previously reported to be aberrantly expressed in tumor cells. It was further showed that inhibition of miR-17-5p and miR-20a by 2′-O-methyl antisense oligoribonucleotides resulted in the induction of senescent phenotypes in WI-38 cells.
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References
Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621
Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740
Ben-Porath I, Weinberg RA (2004) When cells get stressed: an integrative view of cellular senescence. J Clin Invest 113:8–13
Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120:513–522
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367
Jeyapalan JC, Sedivy JM (2008) Cellular senescence and organismal aging. Mech Ageing Dev 129:467–474
Hayflick L (1985) Theories of biological aging. Exp Gerontol 20:145–159
Campisi J (2001) Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol 11:S27–S31
Wright WE, Shay JW (2001) Cellular senescence as a tumor-protection mechanism: the essential role of counting. Curr Opin Genet Dev 11:98–103
He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, Jackson AL, Linsley PS, Chen C, Lowe SW, Cleary MA, Hannon GJ (2007) A microRNA component of the p53 tumour suppressor network. Nature 447:1130–1134
Tazawa H, Tsuchiya N, Izumiya M, Nakagama H (2007) Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci USA 104:15472–15477
Brosh R, Shalgi R, Liran A, Landan G, Korotayev K, Nguyen GH, Enerly E, Johnsen H, Buganim Y, Solomon H, Goldstein I, Madar S, Goldfinger N, Borresen-Dale AL, Ginsberg D, Harris CC, Pilpel Y, Oren M, Rotter V (2008) p53-Repressed miRNAs are involved with E2F in a feed-forward loop promoting proliferation. Mol Syst Biol 4:229
Cong YS, Fan E, Wang E (2006) Simultaneous proteomic profiling of four different growth states of human fibroblasts, using amine-reactive isobaric tagging reagents and tandem mass spectrometry. Mech Ageing Dev 127:332–343
Thomson JM, Parker J, Perou CM, Hammond SM (2004) A custom microarray platform for analysis of microRNA gene expression. Nat Method 1:47–53
Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, Mahuvakar VR, Andersen MR, Lao KQ, Livak KJ, Guegler KJ (2005) Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res 33:e179
da Rocha ST, Edwards CA, Ito M, Ogata T, Ferguson-Smith AC (2008) Genomic imprinting at the mammalian Dlk1-Dio3 domain. Trends Genet 24:306–316
Saito Y, Liang G, Egger G, Friedman JM, Chuang JC, Coetzee GA, Jones PA (2006) Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 9:435–443
Mendell JT (2008) miRiad roles for the miR-17–92 cluster in development and disease. Cell 133:217–222
Tanzer A, Stadler PF (2004) Molecular evolution of a microRNA cluster. J Mol Biol 339:327–335
Ota A, Tagawa H, Karnan S, Tsuzuki S, Karpas A, Kira S, Yoshida Y, Seto M (2004) Identification and characterization of a novel gene, C13orf25, as a target for 13q31–q32 amplification in malignant lymphoma. Cancer Res 64:3087–3095
He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM (2005) A microRNA polycistron as a potential human oncogene. Nature 435:828–833
Landais S, Landry S, Legault P, Rassart E (2007) Oncogenic potential of the miR-106–363 cluster and its implication in human T-cell leukemia. Cancer Res 67:5699–5707
Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, Iliopoulos D, Pilozzi E, Liu CG, Negrini M, Cavazzini L, Volinia S, Alder H, Ruco LP, Baldassarre G, Croce CM, Vecchione A (2008) E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell 13:272–286
Maes OC, Sarojini H, Wang E (2009) Stepwise up-regulation of microRNA expression levels from replicating to reversible and irreversible growth arrest states in WI-38 human fibroblasts. J Cell Physiol 221:109–119
Bonifacio LN, Jarstfer MB (2010) MiRNA profile associated with replicative senescence, extended cell culture, and ectopic telomerase expression in human foreskin fibroblasts. PLoS One 5(9):e12519
Hua Z, Lv Q, Ye W, Wong CK, Cai G, Gu D, Ji Y, Zhao C, Wang J, Yang BB, Zhang Y (2006) MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia. PLoS One 1:e116
Satzger I, Mattern A, Kuettler U, Weinspach D, Voelker B, Kapp A, Gutzmer R (2010) MicroRNA-15b represents an independent prognostic parameter and is correlated with tumor cell proliferation and apoptosis in malignant melanoma. Int J Cancer 126:2553–2562
Wang X, Tang S, Le SY, Lu R, Rader JS, Meyers C, Zheng ZM (2008) Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth. PLoS One 3:e2557
Xi Y, Formentini A, Chien M, Weir DB, Russo JJ, Ju J, Kornmann M, Ju J (2006) Prognostic values of microRNAs in colorectal cancer. Biomark Insights 2:113–121
Xia L, Zhang D, Du R, Pan Y, Zhao L, Sun S, Hong L, Liu J, Fan D (2008) miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int J Cancer 123:372–379
O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435:839–843
Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103:2257–2261
Kim YK, Yu J, Han TS, Park SY, Namkoong B, Kim DH, Hur K, Yoo MW, Lee HJ, Yang HK, Kim VN (2009) Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer. Nucleic Acids Res 37:1672–1681
Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH, Kim JW, Kim S (2008) MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res 14:2690–2695
Woods K, Thomson JM, Hammond SM (2007) Direct regulation of an oncogenic micro-RNA cluster by E2F transcription factors. J Biol Chem 282:2130–2134
Sylvestre Y, De Guire V, Querido E, Mukhopadhyay UK, Bourdeau V, Major F, Ferbeyre G, Chartrand P (2007) An E2F/miR-20a autoregulatory feedback loop. J Biol Chem 282:2135–2143
Pickering MT, Stadler BM, Kowalik TF (2009) miR-17 and miR-20a temper an E2F1-induced G1 checkpoint to regulate cell cycle progression. Oncogene 28:140–145
Poliseno L, Pitto L, Simili M, Mariani L, Riccardi L, Ciucci A, Rizzo M, Evangelista M, Mercatanti A, Pandolfi PP, Rainaldi G (2008) The proto-oncogene LRF is under post-transcriptional control of MiR-20a: implications for senescence. PLoS One 3:e2542
Dimri GP, Itahana K, Acosta M, Campisi J (2000) Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14(ARF) tumor suppressor. Mol Cell Biol 20:273–285
Park C, Lee I, Kang WK (2006) E2F–1 is a critical modulator of cellular senescence in human cancer. Int J Mol Med 17:715–720
Hackl M, Brunner S, Fortschegger K, Schreiner C, Micutkova L, Muck C, Laschober GT, Lepperdinger G, Sampson N, Berger P, Herndler-Brandstetter D, Wieser M, Kuhnel H, Strasser A, Rinnerthaler M, Breitenbach M, Mildner M, Eckhart L, Tschachler E, Trost A, Bauer JW, Papak C, Trajanoski Z, Scheideler M, Grillari-Voglauer R, Grubeck-Loebenstein B, Jansen-Durr P, Grillari J (2010) miR-17, miR-19b, miR-20a, and miR-106a are down-regulated in human aging. Aging Cell 9:291–296
Acknowledgments
This study was supported by the grants from the “973” Project of the Ministry of Science and Technology [2007CB507402, 2007CB914402, 2010CB912802] and the grants from the National Natural Science Foundation of China [30671065, 30871258].
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11010_2011_763_MOESM1_ESM.jpg
Expression profile of selected miRNAs in young replicating, senescent and quiescent cells by stem-loop qRT–PCR. Relative expression levels of the miRNAs (miR-15b, miR-17-5p, miR-20a, miR-25, miR-93, miR-106a, miR-127-3p, mir-329, miR-409-3p, miR-487b, miR-493*, miR-495) identified by microarray were analyzed by stem-loop qRT–PCR in different growth states of WI-38 cells. U6 RNA was used for normalization. Data are presented as the mean ± SD from three independent experiments. (JPEG 137 kb)
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Wang, M., Cheng, Z., Tian, T. et al. Differential expression of oncogenic miRNAs in proliferating and senescent human fibroblasts. Mol Cell Biochem 352, 271–279 (2011). https://doi.org/10.1007/s11010-011-0763-z
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DOI: https://doi.org/10.1007/s11010-011-0763-z