Abstract
Resistance to anoikis, the subtype of apoptosis induced by lack of matrix adhesion, contributes to malignant transformation and development of metastasis. MicroRNAs play key regulatory roles in tumorigenesis and metastasis. In this study, we described that miR-26a, which is usually downregulated in tumor cells, is involved in the acquisition of anoikis-resistance of human esophageal adenocarcinoma (EA) cells. Results of qRT-PCR in clinical samples showed that downregulated miR-26a expression is related to tumorigenesis and metastasis of EA. In vitro experiments determined that miR-26a directly participates in the regulation of cell cycle and anoikis of human EA OE33 cells. Further, we identified that Rb1 is the direct functional target of miR-26a, and revealed that the reduction of miR-26a expression leads to increased Rb1 protein level and thus inhibits the function of E2F1, by which it influences the phenotypes of cell cycle and anoikis. The findings we reported here presented the evidence that miR-26a may be involved in regulation of anoikis-resistance of EA cells. Targeting miR-26a may provide a novel strategy to inhibit metastasis.






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References
Pohl H, Sirovich B, Welch HG et al (2010) Esophageal adenocarcinoma incidence: are we reaching the peak? Cancer Epidemiol Biomarkers Prev 19(6):1468–1470
Mariette C, Balon JM, Piessen G et al (2003) Pattern of recurrence following complete resection of esophageal carcinoma and factors predictive of recurrent disease. Cancer 97(7):1616–1623
Horbinski C, Mojesky C, Kyprianou N (2010) Live free or die: tales of homeless (cells) in cancer. Am J Pathol 177(3):1044–1052
Frisch SM, Screaton RA (2001) Anoikis mechanisms. Curr Opin Cell Biol 13(5):555–562
Simpson CD, Anyiwe K, Schimmer AD (2008) Anoikis resistance and tumor metastasis. Cancer Lett 272(2):177–185
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674
Inui M, Martello G, Piccolo S (2010) MicroRNA control of signal transduction. Nat Rev Mol Cell Biol 11(4):252–263
Korpal M, Kang Y (2008) The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis. RNA Biol 5(3):115–119
Krichevsky AM, Gabriely G (2009) miR-21: a small multi-faceted RNA. J Cell Mol Med 13(1):39–53
Schafer ZT, Grassian AR, Song L et al (2009) Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461(7260):109–113
Gros SJ, Dohrmann T, Peldschus K et al (2010) Complementary use of fluorescence and magnetic resonance imaging of metastatic esophageal cancer in a novel orthotopic mouse model. Int J Cancer 126(11):2671–2681
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402–408
Zhang YF, Li XH, Shi YQ (2011) CIAPIN1 confers multidrug resistance through up-regulation of MDR-1 and Bcl-L in LoVo/Adr cells and is independent of p53. Oncol Rep 25(4):1091–1098
Dong LW, Yang GZ, Pan YF et al (2011) The oncoprotein p28(GANK) establishes a positive feedback loop in β-catenin signaling. Cell Res 21(8):1248–1261
Ji J, Shi J, Budhu A, Yu Z et al (2009) MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med 361(15):1437–1447
Villanueva A, Hoshida Y, Toffanin S et al (2010) New strategies in hepatocellular carcinoma: genomic prognostic markers. Clin Cancer Res 16(9):4688–4694
Ciarapica R, Russo G, Verginelli F et al (2009) Deregulated expression of miR-26a and Ezh2 in rhabdomyosarcoma. Cell Cycle 8(1):172–175
Heinzelmann J, Henning B, Sanjmyatav J et al (2011) Specific miRNA signatures are associated with metastasis and poor prognosis in clear cell renal cell carcinoma. World J Urol 29(3):367–373
Kota J, Chivukula RR, O’Donnell KA et al (2009) Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell 137(6):1005–1017
Kim H, Huang W, Jiang X et al (2010) Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship. Proc Natl Acad Sci USA 107(5):2183–2188
Du W, Searle JS (2009) The rb pathway and cancer therapeutics. Curr Drug Targets 10(7):581–589
Rogoff HA, Kowalik TF (2004) Life, death and E2F: linking proliferation control and DNA damage signaling via E2F1. Cell Cycle 3(7):845–846
Tanaka H, Matsumura I, Ezoe S et al (2002) E2F1 and c-Myc potentiate apoptosis through inhibition of NF-kappaB activity that facilitates MnSOD-mediated ROS elimination. Mol Cell 9(5):1017–1029
Chen M, Capps C, Willerson JT (2002) E2F-1 regulates nuclear factor-kappaB activity and cell adhesion: potential antiinflammatory activity of the transcription factor E2F-1. Circulation 106(21):2707–2713
Hao H, Zhou HS, McMasters KM (2009) Chemosensitization of tumor cells: inactivation of nuclear factor-kappa B associated with chemosensitivity in melanoma cells after combination treatment with E2F-1 and doxorubicin. Methods Mol Biol 542:301–313
Hwang HC, Clurman BE (2005) Cyclin E in normal and neoplastic cell cycles. Oncogene 24(17):2776–2786
Ohtani K, DeGregori J, Nevins JR (1995) Regulation of the cyclin E gene by transcription factor E2F1. Proc Natl Acad Sci USA 92(26):12146–12150
Ak P, Levine AJ (2010) p53 and NF-κB: different strategies for responding to stress lead to a functional antagonism. FASEB J 24(10):3643–3652
Sander S, Bullinger L, Wirth T (2009) Repressing the repressor: a new mode of MYC action in lymphomagenesis. Cell Cycle 8(4):556–559
Wong CF, Tellam RL (2008) MicroRNA-26a targets the histone methyltransferase Enhancer of Zeste homolog 2 during myogenesis. J Biol Chem 283(15):9836–9843
Wu Z, Yu Q (2009) E2F1-mediated apoptosis as a target of cancer therapy. Curr Mol Pharmacol 2(2):149–160
Mahidhara RS, Queiroz De Oliveira PE, Kohout J et al (2005) Altered trafficking of Fas and subsequent resistance to Fas-mediated apoptosis occurs by a wild-type p53 independent mechanism in esophageal adenocarcinoma. J Surg Res 123(2):302–311
Korotayev K, Ginsberg D (2008) Many pathways to apoptosis: E2F1 regulates splicing of apoptotic genes. Cell Death Differ 15(2):1813–1814
Gartel AL, Tyner AL (2002) The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther 1(8):639–649
Hiromura K, Pippin JW, Fero ML (1999) Modulation of apoptosis by the cyclin-dependent kinase inhibitor p27(Kip1). J Clin Invest 103(5):597–604
Pucci B, Kasten M, Giordano A (2000) Cell cycle and apoptosis. Neoplasia 2(4):291–299
Collins NL, Reginato MJ, Paulus JK (2005) G1/S cell cycle arrest provides anoikis resistance through Erk-mediated Bim suppression. Mol Cell Biol 25(12):5282–5291
Lin Y, Bai L, Chen W, Xu S (2010) The NF-kappaB activation pathways, emerging molecular targets for cancer prevention and therapy. Expert Opin Ther Targets 14(1):45–55
Karin M, Greten FR (2005) NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5(10):749–759
Vachon PH (2011) Integrin signaling, cell survival, and anoikis: distinctions, differences, and differentiation. J Signal Transduct 2011:738137
Acknowledgments
This work was supported by the National Foundation of Natural Sciences, China (No. 81101533, No. 81071727 and No. 81170356) and China Postdoctoral Science Foundation (No. 20100481468 and No. 201104755).
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Ya-Fei Zhang and An-Ran Zhang contributed equally to this work.
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Zhang, YF., Zhang, AR., Zhang, BC. et al. MiR-26a regulates cell cycle and anoikis of human esophageal adenocarcinoma cells through Rb1-E2F1 signaling pathway. Mol Biol Rep 40, 1711–1720 (2013). https://doi.org/10.1007/s11033-012-2222-7
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DOI: https://doi.org/10.1007/s11033-012-2222-7