Journal of Translational Medicine | |
Mir-208 promotes cell proliferation by repressing SOX6 expression in human esophageal squamous cell carcinoma | |
Jianyong Yang4  Yong Gu3  Shiqiu Xiong1  Wei Chen4  Junwei Ou3  Liangshuai Liu4  Bing Zhang4  Dayong Zheng2  Heping Li5  | |
[1] Department of Biochemistry, University of Leicester, Leicester, UK;Department of Oncology, Nanfang Hosptial, Southern Medical University, Guangzhou 510515, P.R. China;Department of Thoracic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, P.R. China;Department of Medical Imaging, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, P.R. China;Department of Oncology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, P.R. China | |
关键词: Proliferation; Esophageal squamous cell carcinoma; SOX6; miR-208; | |
Others : 1148685 DOI : 10.1186/1479-5876-12-196 |
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received in 2014-01-05, accepted in 2014-07-01, 发布年份 2014 | |
【 摘 要 】
Background
Esophageal squamous cell carcinoma (ESCC) is the major histological type of esophageal cancer in developing countries. The prognosis and survival rate of ESCC are very poor. Recently, microRNAs (miRNAs) have emerged as important regulators of cancer cell biological processes. To better understanding the molecular mechanisms by which they regulate the behavior of cancer cells is needed.
Methods
The expression of miR-208 was examined in ESCC cell lines and tumor tissues by real-time PCR. Proliferation capability of ESCC cells upon regulation of miR-208 expression was detected by MTT assay, colony formation assay, anchorage-independent growth ability assay and flow cytometry analysis. The target of miR-208 was determined by western blotting analysis, luciferase reporter assay and real-time PCR.
Results
miR-208 was upregulated in ESCC cell lines and tissues. Overexpression of miR-208 in ESCC cells increased cell proliferation, tumorigenicity and cell cycle progression, whereas inhibition of miR-208 reduced cells proliferation, tumorigenicity and cell cycle progression. Additionally, SOX6 was identified as a direct target of miR-208. Ectopic expression of miR-208 led to downregulation of SOX6 protein, which resulted in the downregulation of p21, upregulation of cyclin D1 and phosphorylation of Rb.
Conclusions
These results suggest that miR-208 represents a potential onco-miR and participates in ESCC carcinogenesis by suppressing SOX6 expression.
【 授权许可】
2014 Li et al.; licensee BioMed Central Ltd.
【 预 览 】
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Figure 2. | 123KB | Image | download |
Figure 1. | 55KB | Image | download |
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【 参考文献 】
- [1]Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics. 2002. CA Cancer J Clin 2005, 55:74-108.
- [2]Enzinger PC, Mayer RJ: Esophageal cancer. N Engl J Med 2003, 349:2241-2252.
- [3]Lee KH, Goan YG, Hsiao M, Lee CH, Jian SH, Lin JT, Chen YL, Lu PJ: MicroRNA-373 (miR-373) post-transcriptionally regulates large tumor suppressor, homolog 2 (LATS2) and stimulates proliferation in human esophageal cancer. Exp Cell Res 2009, 315:2529-2538.
- [4]Xing D, Tan W, Lin D: Genetic polymorphisms and susceptibility to esophageal cancer among Chinese population (review). Oncol Rep 2003, 10:1615-1623.
- [5]Mizushima T, Nakagawa H, Kamberov YG, Wilder EL, Klein PS, Rustgi AK: Wnt-1 but not epidermal growth factor induces beta-catenin/T-cell factor-dependent transcription in esophageal cancer cells. Cancer Res 2002, 62:277-282.
- [6]Yang L, Leung AC, Ko JM, Lo PH, Tang JC, Srivastava G, Oshimura M, Stanbridge EJ, Daigo Y, Nakamura Y, Tang CM, Lau KW, Law S, Lung ML: Tumor suppressive role of a 2.4 Mb 9q33-q34 critical region and DEC1 in esophageal squamous cell carcinoma. Oncogene 2005, 24:697-705.
- [7]Ambros V: The functions of animal microRNAs. Nature 2004, 431:350-355.
- [8]Bartel DP: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004, 116:281-297.
- [9]Calin GA, Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer 2006, 6:857-866.
- [10]Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM: miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A 2005, 102:13944-13949.
- [11]Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, Nuovo G, Raychaudhury A, Newton HB, Chiocca EA, Lawler S: Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal. Cancer Res 2008, 68:9125-9130.
- [12]Cho WC: OncomiRs: the discovery and progress of microRNAs in cancers. Mol Cancer 2007, 6:60.
- [13]Hamada-Kanazawa M, Ishikawa K, Ogawa D, Kanai M, Kawai Y, Narahara M, Miyake M: Suppression of Sox6 in P19 cells leads to failure of neuronal differentiation by retinoic acid and induces retinoic acid-dependent apoptosis. FEBS Lett 2004, 577:60-66.
- [14]Iguchi H, Urashima Y, Inagaki Y, Ikeda Y, Okamura M, Tanaka T, Uchida A, Yamamoto TT, Kodama T, Sakai J: SOX6 suppresses cyclin D1 promoter activity by interacting with beta-catenin and histone deacetylase 1, and its down-regulation induces pancreatic beta-cell proliferation. J Biol Chem 2007, 282:19052-19061.
- [15]Qin YR, Tang H, Xie F, Liu H, Zhu Y, Ai J, Chen L, Li Y, Kwong DL, Fu L, Guan XY: Characterization of tumor-suppressive function of SOX6 in human esophageal squamous cell carcinoma. Clin Cancer Res 2010, 17:46-55.
- [16]Guo X, Yang M, Gu H, Zhao J, Zou L: Decreased expression of SOX6 confers a poor prognosis in hepatocellular carcinoma. Cancer Epidemiol 2013, 37:732-736.
- [17]Andl CD, Mizushima T, Nakagawa H, Oyama K, Harada H, Chruma K, Herlyn M, Rustgi AK: Epidermal growth factor receptor mediates increased cell proliferation, migration, and aggregation in esophageal keratinocytes in vitro and in vivo. J Biol Chem 2003, 278:1824-1830.
- [18]Hahn WC, Dessain SK, Brooks MW, King JE, Elenbaas B, Sabatini DM, De Caprio JA, Weinberg RA: Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol Cell Biol 2002, 22:2111-2123.
- [19]Li J, Zhang N, Song LB, Liao WT, Jiang LL, Gong LY, Wu J, Yuan J, Zhang HZ, Zeng MS, Li M: Astrocyte elevated gene-1 is a novel prognostic marker for breast cancer progression and overall patient survival. Clin Cancer Res 2008, 14:3319-3326.
- [20]Esquela-Kerscher A, Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 2006, 6:259-269.
- [21]Rabinowits G, Gercel-Taylor C, Day JM, Taylor DD, Kloecker GH: Exosomal microRNA: a diagnostic marker for lung cancer. Clin Lung Cancer 2009, 10:42-46.
- [22]Stahlhut Espinosa CE, Slack FJ: The role of microRNAs in cancer. Yale J Biol Med 2006, 79:131-140.
- [23]Blenkiron C, Goldstein LD, Thorne NP, Spiteri I, Chin SF, Dunning MJ, Barbosa-Morais NL, Teschendorff AE, Green AR, Ellis IO, Tavaré S, Caldas C, Miska EA: MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype. Genome Biol 2007, 8:R214.
- [24]Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A, O'Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M: Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 2008, 105:10513-10518.
- [25]Cai B, Pan Z, Lu Y: The roles of microRNAs in heart diseases: a novel important regulator. Curr Med Chem 2010, 17:407-411.
- [26]Han M, Toli J, Abdellatif M: MicroRNAs in the cardiovascular system. Curr Opin Cardiol 2011, 26:181-189.
- [27]Malizia AP, Wang DZ: MicroRNAs in cardiomyocyte development. Wiley Interdiscip Rev Syst Biol Med 2011, 3:183-190.
- [28]Montgomery RL, Hullinger TG, Semus HM, Dickinson BA, Seto AG, Lynch JM, Stack C, Latimer PA, Olson EN, van Rooij E: Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation 2011, 124:1537-1547.
- [29]Itoh T, Takeda S, Akao Y: MicroRNA-208 modulates BMP-2-stimulated mouse preosteoblast differentiation by directly targeting V-ets erythroblastosis virus E26 oncogene homolog 1. J Biol Chem 2010, 285:27745-27752.
- [30]Doench JG, Sharp PA: Specificity of microRNA target selection in translational repression. Genes Dev 2004, 18:504-511.
- [31]Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M, Rajewsky N: Combinatorial microRNA target predictions. Nat Genet 2005, 37:495-500.
- [32]Shukla GC, Singh J, Barik S: MicroRNAs: processing, maturation, target recognition and regulatory functions. Mol Cell Pharmacol 2011, 3:83-92.
- [33]Rice TW, Zuccaro G Jr, Adelstein DJ, Rybicki LA, Blackstone EH, Goldblum JR: Esophageal carcinoma: depth of tumor invasion is predictive of regional lymph node status. Ann Thorac Surg 1998, 65:787-792.