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01-12-2016 | Original Article

MiRNA-221-3p desensitizes pancreatic cancer cells to 5-fluorouracil by targeting RB1

Authors: Lijun Zhao, Dongling Zou, Xueju Wei, Lanlan Wang, Yuanyuan Zhang, Siqi Liu, Yanmin Si, Hualu Zhao, Fang Wang, Jia Yu, Yanni Ma, Guotao Sun

Published in: Tumor Biology | Issue 12/2016

Abstract

Pancreatic cancer is a highly lethal disease due to its rapid dissemination and resistance to conventional chemotherapy. MicroRNAs (miRNAs) are emerging as novel regulators of chemoresistance, which modulate the expression of drug resistance-related genes. MiRNA-221 has been reported to be associated with chemoresistance in various types of cancer. But the detailed molecular mechanism about miR-221-3p regulating 5-fluorouracil (5-FU) resistance in human pancreatic cancer remains to be clarified. In this study, we investigated the association between miR-221-3p expression and 5-FU sensitivity. Studies on pancreatic cancer cell lines suggested an increased 5-FU resistance with miR-221-3p over-expression. In addition, the results indicated that miR-221-3p down-regulated RB1 expression by directly binding to its 3′-UTR and therefore caused increased several aspects of pancreatic cancer pathogenesis, including proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Collectively, our findings revealed the important role of miR-221-3p in promoting 5-FU resistance of pancreatic cancer cells and provided a potential therapeutic target for pancreatic cancer.

Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29. doi:10.3322/caac.21208.CrossRefPubMed

Cartwright T, Richards DA, Boehm KA. Cancer of the pancreas: are we making progress? A review of studies in the US Oncology Research Network. Cancer Control. 2008;15(4):308–13.PubMed

Li W, Ma Q, Liu J, Han L, Ma G, Liu H, et al. Hyperglycemia as a mechanism of pancreatic cancer metastasis. Front Biosci (Landmark Ed). 2012;17:1761–74.CrossRef

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi:10.1016/j.cell.2011.02.013.CrossRefPubMed

Long J, Zhang Y, Yu X, Yang J, LeBrun DG, Chen C, et al. Overcoming drug resistance in pancreatic cancer. Expert Opin Ther Targets. 2011;15(7):817–28. doi:10.1517/14728222.2011.566216.CrossRefPubMedPubMedCentral

Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.CrossRefPubMed

Chen K, Rajewsky N. The evolution of gene regulation by transcription factors and microRNAs. Nat Rev Genet. 2007;8(2):93–103.CrossRefPubMed

Lu H, Buchan RJ, Cook SA. MicroRNA-223 regulates Glut4 expression and cardiomyocyte glucose metabolism. Cardiovasc Res. 2010;86(3):410–20. doi:10.1093/cvr/cvq010.CrossRefPubMed

Ma F, Liu X, Li D, Wang P, Li N, Lu L, et al. MicroRNA-466l upregulates IL-10 expression in TLR-triggered macrophages by antagonizing RNA-binding protein tristetraprolin-mediated IL-10 mRNA degradation. J Immunol. 2010;184(11):6053–9. doi:10.4049/jimmunol.0902308.CrossRefPubMed

10.

Liu J, Valencia-Sanchez MA, Hannon GJ, Parker R. MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nat Cell Biol. 2005;7(7):719–23.CrossRefPubMedPubMedCentral

11.

Saxena S, Jonsson ZO, Dutta A. Small RNAs with imperfect match to endogenous mRNA repress translation. Implications for off-target activity of small inhibitory RNA in mammalian cells. J Biol Chem. 2003;278(45):44312–9. doi:10.1074/jbc.M307089200.CrossRefPubMed

12.

Ambros V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell. 2003;113(6):673–6.CrossRefPubMed

13.

Hummel R, Hussey DJ, Haier J. MicroRNAs: predictors and modifiers of chemo- and radiotherapy in different tumour types. Eur J Cancer. 2010;46(2):298–311. doi:10.1016/j.ejca.2009.10.027.CrossRefPubMed

14.

Lima RT, Busacca S, Almeida GM, Gaudino G, Fennell DA, Vasconcelos MH. MicroRNA regulation of core apoptosis pathways in cancer. Eur J Cancer. 2011;47(2):163–74. doi:10.1016/j.ejca.2010.11.005.CrossRefPubMed

15.

Schoof CR, Botelho EL, Izzotti A, Vasques Ldos R. MicroRNAs in cancer treatment and prognosis. Am J Cancer Res. 2012;2(4):414–33.PubMedPubMedCentral

16.

Garofalo M, Quintavalle C, Di Leva G, Zanca C, Romano G, Taccioli C, et al. MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer. Oncogene. 2008;27(27):3845–55. doi:10.1038/onc.2008.6.CrossRefPubMed

17.

Zhao JJ, Lin J, Yang H, Kong W, He L, Ma X, et al. MicroRNA-221/222 negatively regulates estrogen receptor alpha and is associated with tamoxifen resistance in breast cancer. J Biol Chem. 2008;283(45):31079–86. doi:10.1074/jbc.CrossRefPubMedPubMedCentral

18.

Gramantieri L, Fornari F, Ferracin M, Veronese A, Sabbioni S, Calin GA, et al. MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality. Clin Cancer Res. 2009;15(16):5073–81. doi:10.1158/1078-0432.CCR-09-0092.CrossRefPubMedPubMedCentral

19.

Lu X, Zhao P, Zhang C, Fu Z, Chen Y, Lu A, et al. Analysis of miR-221 and p27 expression in human gliomas. Mol Med Rep. 2009;2(4):651–6. doi:10.3892/mmr_00000152.PubMed

20.

Zhang C, Kang C, You Y, Pu P, Yang W, Zhao P, et al. Co-suppression of miR-221/222 cluster suppresses human glioma cell growth by targeting p27kip1 in vitro and in vivo. Int J Oncol. 2009;34(6):1653–60.PubMed

21.

Zhang C, Zhang J, Hao J, Shi Z, Wang Y, Han L, et al. High level of miR-221/222 confers increased cell invasion and poor prognosis in glioma. J Transl Med. 2012;10:119. doi:10.1186/1479-5876-10-119.CrossRefPubMedPubMedCentral

22.

Zhang J, Han L, Ge Y, Zhou X, Zhang A, Zhang C, et al. miR-221/222 promote malignant progression of glioma through activation of the Akt pathway. Int J Oncol. 2010;36(4):913–20.PubMed

23.

Papaconstantinou IG, Manta A, Gazouli M, Lyberopoulou A, Lykoudis PM, Polymeneas G, et al. Expression of microRNAs in patients with pancreatic cancer and its prognostic significance. Pancreas. 2013;42(1):67–71. doi:10.1097/MPA.0b013e3182592ba7.CrossRefPubMed

24.

Sabbah M, Emami S, Redeuilh G, Julien S, Prevost G, Zimber A, et al. Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers. Drug Resist Updat. 2008;11(4–5):123–51. doi:10.1016/j.drup.2008.07.001.CrossRefPubMed

25.

Fuchs BC, Fujii T, Dorfman JD, Goodwin JM, Zhu AX, Lanuti M, et al. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Res. 2008;68(7):2391–9. doi:10.1158/0008-5472.CrossRefPubMed

26.

Christiansen JJ, Rajasekaran AK. Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res. 2006;66(17):8319–26.CrossRefPubMed

27.

Kong D, Li Y, Wang Z, Sarkar FH. Cancer stem cells and epithelial-to-mesenchymal transition (EMT)-phenotypic cells: are they cousins or twins? Cancers (Basel). 2011;3(1):716–29. doi:10.3390/cancers30100716.CrossRef

28.

Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133(4):704–15. doi:10.1016/j.cell.2008.03.027.CrossRefPubMedPubMedCentral

29.

Wang Z, Li Y, Ahmad A, Banerjee S, Azmi AS, Kong D, et al. Pancreatic cancer: understanding and overcoming chemoresistance. Nat Rev Gastroenterol Hepatol. 2011;8(1):27–33. doi:10.1038/nrgastro.2010.188.CrossRefPubMed

30.

Castellanos JA, Merchant NB, Nagathihalli NS. Emerging targets in pancreatic cancer: epithelial-mesenchymal transition and cancer stem cells. Onco Targets Ther. 2013;6:1261–7. doi:10.2147/OTT.PubMedPubMedCentral

31.

Cheng GZ, Chan J, Wang Q, Zhang W, Sun CD, Wang LH. Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res. 2007;67(5):1979–87 doi:67/5/1979.CrossRefPubMed

32.

Jiang JH, Liu C, Cheng H, Lu Y, Qin Y, YF X, et al. Epithelial-mesenchymal transition in pancreatic cancer: is it a clinically significant factor? Biochim Biophys Acta. 2015;1855(1):43–9. doi:10.1016/j.bbcan.2014.11.004.PubMed

33.

Cano A, Nieto MA. Non-coding RNAs take centre stage in epithelial-to-mesenchymal transition. Trends Cell Biol. 2008;18(8):357–9. doi:10.1016/j.tcb.2008.05.005.CrossRefPubMed

34.

Garzon R, Fabbri M, Cimmino A, Calin GA, Croce CM. MicroRNA expression and function in cancer. Trends Mol Med. 2006;12(12):580–7.CrossRefPubMed

35.

Kozomara A, Griffiths-Jones S. miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 2014;42(Database issue):D68–73. doi:10.1093/nar/gkt1181.CrossRefPubMed

36.

Li JH, Luo N, Zhong MZ, Xiao ZQ, Wang JX, Yao XY, et al. Inhibition of microRNA-196a might reverse cisplatin resistance of A549/DDP non-small-cell lung cancer cell line. Tumour Biol. 2015. doi:10.1007/s13277-015-4017-7.

37.

Liu RL, Dong Y, Deng YZ, Wang WJ, Li WD. Tumor suppressor miR-145 reverses drug resistance by directly targeting DNA damage-related gene RAD18 in colorectal cancer. Tumour Biol. 2015;36(7):5011–9. doi:10.1007/s13277-015-3152-5.CrossRefPubMed

38.

Li Z, Yu X, Shen J, Jiang Y. MicroRNA dysregulation in uveal melanoma: a new player enters the game. Oncotarget. 2015;6(7):4562–8.CrossRefPubMedPubMedCentral

39.

Bader AG, Brown D, Winkler M. The promise of microRNA replacement therapy. Cancer Res. 2010;70(18):7027–30. doi:10.1158/0008-5472.CrossRefPubMedPubMedCentral

40.

Pencheva N, Tavazoie SF. Control of metastatic progression by microRNA regulatory networks. Nat Cell Biol. 2013;15(6):546–54. doi:10.1038/ncb2769.CrossRefPubMedPubMedCentral

41.

Sivadas VP, Kannan S. The microRNA networks of TGFbeta signaling in cancer. Tumour Biol. 2014;35(4):2857–69. doi:10.1007/s13277-013-1481-9.CrossRefPubMed

42.

Garzon R, Calin GA, Croce CM. MicroRNAs in cancer. Annu Rev Med. 2009;60:167–79. doi:10.1146/annurev.med.59.053006.104707.CrossRefPubMed

43.

Davis BN, Hilyard AC, Nguyen PH, Lagna G, Hata A. Induction of microRNA-221 by platelet-derived growth factor signaling is critical for modulation of vascular smooth muscle phenotype. J Biol Chem. 2009;284(6):3728–38. doi:10.1074/jbc.M808788200.CrossRefPubMedPubMedCentral

44.

Kawaguchi T, Komatsu S, Ichikawa D, Morimura R, Tsujiura M, Konishi H, et al. Clinical impact of circulating miR-221 in plasma of patients with pancreatic cancer. Br J Cancer. 2013;108(2):361–9. doi:10.1038/bjc.2012.546.CrossRefPubMedPubMedCentral

45.

le Sage C, Nagel R, Egan DA, Schrier M, Mesman E, Mangiola A, et al. Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J. 2007;26(15):3699–708.CrossRefPubMedPubMedCentral

46.

Stinson S, Lackner MR, Adai AT, Yu N, Kim HJ, O'Brien C, et al. TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer. Sci Signal. 2011;4(177):ra41. doi:10.1126/scisignal.CrossRefPubMed

47.

Ciafre SA, Galardi S, Mangiola A, Ferracin M, Liu CG, Sabatino G, et al. Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun. 2005;334(4):1351–8.CrossRefPubMed

48.

Besson A, Gurian-West M, Schmidt A, Hall A, Roberts JM. p27Kip1 modulates cell migration through the regulation of RhoA activation. Genes Dev. 2004;18(8):862–76. doi:10.1101/gad.1185504.CrossRefPubMedPubMedCentral

49.

Nikiforova MN, Tseng GC, Steward D, Diorio D, Nikiforov YE. MicroRNA expression profiling of thyroid tumors: biological significance and diagnostic utility. J Clin Endocrinol Metab. 2008;93(5):1600–8. doi:10.1210/jc.2007-2696.CrossRefPubMedPubMedCentral

50.

Pang Y, Young CY, Yuan H. MicroRNAs and prostate cancer. Acta Biochim Biophys Sin Shanghai. 2010;42(6):363–9.CrossRefPubMed

51.

Urbich C, Kuehbacher A, Dimmeler S. Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc Res. 2008;79(4):581–8. doi:10.1093/cvr/cvn156.CrossRefPubMed

52.

Vasilatou D, Papageorgiou S, Pappa V, Papageorgiou E, Dervenoulas J. The role of microRNAs in normal and malignant hematopoiesis. Eur J Haematol. 2010;84(1):1–16. doi:10.1111/j.1600-0609.2009.01348.x.CrossRefPubMed

53.

Hwang MS, Yu N, Stinson SY, Yue P, Newman RJ, Allan BB, et al. miR-221/222 targets adiponectin receptor 1 to promote the epithelial-to-mesenchymal transition in breast cancer. PLoS One. 2013;8(6):e66502. doi:10.1371/journal.pone.0066502.CrossRefPubMedPubMedCentral

54.

Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17(5):548–58.CrossRefPubMed

55.

Murphree AL, Benedict WF. Retinoblastoma: clues to human oncogenesis. Science. 1984;223(4640):1028–33.CrossRefPubMed

56.

Shao Z, Robbins PD. Differential regulation of E2F and Sp1-mediated transcription by G1 cyclins. Oncogene. 1995;10(2):221–8.PubMed

57.

Indovina P, Pentimalli F, Casini N, Vocca I, A. G. .RB1 dual role in proliferation and apoptosis: cell fate control and implications for cancer therapy. Oncotarget. 2015;6(20):17873–90.CrossRefPubMedPubMedCentral

Title: MiRNA-221-3p desensitizes pancreatic cancer cells to 5-fluorouracil by targeting RB1
Authors: Lijun Zhao
Dongling Zou
Xueju Wei
Lanlan Wang
Yuanyuan Zhang
Siqi Liu
Yanmin Si
Hualu Zhao
Fang Wang
Jia Yu
Yanni Ma
Guotao Sun
Publication date: 01-12-2016
Publisher: Springer Netherlands
Published in: Tumor Biology / Issue 12/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI: https://doi.org/10.1007/s13277-016-5445-8

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