Skip to main content
Erschienen in: Tumor Biology 12/2016

10.10.2016 | Original Article

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

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

Erschienen in: Tumor Biology | Ausgabe 12/2016

Einloggen, um Zugang zu erhalten

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.
Literatur
2.
Zurück zum Zitat 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 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
3.
Zurück zum Zitat 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 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
6.
Zurück zum Zitat Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.CrossRefPubMed Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.CrossRefPubMed
7.
Zurück zum Zitat Chen K, Rajewsky N. The evolution of gene regulation by transcription factors and microRNAs. Nat Rev Genet. 2007;8(2):93–103.CrossRefPubMed Chen K, Rajewsky N. The evolution of gene regulation by transcription factors and microRNAs. Nat Rev Genet. 2007;8(2):93–103.CrossRefPubMed
9.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat Ambros V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell. 2003;113(6):673–6.CrossRefPubMed Ambros V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell. 2003;113(6):673–6.CrossRefPubMed
15.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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
20.
Zurück zum Zitat 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 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
22.
Zurück zum Zitat 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 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.
24.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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
30.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
34.
Zurück zum Zitat 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 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
36.
Zurück zum Zitat 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. 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.
45.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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
50.
Zurück zum Zitat Pang Y, Young CY, Yuan H. MicroRNAs and prostate cancer. Acta Biochim Biophys Sin Shanghai. 2010;42(6):363–9.CrossRefPubMed Pang Y, Young CY, Yuan H. MicroRNAs and prostate cancer. Acta Biochim Biophys Sin Shanghai. 2010;42(6):363–9.CrossRefPubMed
54.
Zurück zum Zitat 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 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.
Zurück zum Zitat Murphree AL, Benedict WF. Retinoblastoma: clues to human oncogenesis. Science. 1984;223(4640):1028–33.CrossRefPubMed Murphree AL, Benedict WF. Retinoblastoma: clues to human oncogenesis. Science. 1984;223(4640):1028–33.CrossRefPubMed
56.
Zurück zum Zitat Shao Z, Robbins PD. Differential regulation of E2F and Sp1-mediated transcription by G1 cyclins. Oncogene. 1995;10(2):221–8.PubMed Shao Z, Robbins PD. Differential regulation of E2F and Sp1-mediated transcription by G1 cyclins. Oncogene. 1995;10(2):221–8.PubMed
57.
Zurück zum Zitat 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 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
Metadaten
Titel
MiRNA-221-3p desensitizes pancreatic cancer cells to 5-fluorouracil by targeting RB1
verfasst von
Lijun Zhao
Dongling Zou
Xueju Wei
Lanlan Wang
Yuanyuan Zhang
Siqi Liu
Yanmin Si
Hualu Zhao
Fang Wang
Jia Yu
Yanni Ma
Guotao Sun
Publikationsdatum
10.10.2016
Verlag
Springer Netherlands
Erschienen in
Tumor Biology / Ausgabe 12/2016
Print ISSN: 1010-4283
Elektronische ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-016-5445-8

Weitere Artikel der Ausgabe 12/2016

Tumor Biology 12/2016 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.