Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

miRNA-193b-5p Suppresses Pancreatic Cancer Cell Proliferation, Invasion, Epithelial Mesenchymal Transition, and Tumor Growth by Inhibiting eEF2K

Author(s): Nilgun Gurbuz, Nermin Kahraman, Hafize Elif Sonmez, Hamada Ahmed Mokhlis, Pinar Aslan Kosar and Bulent Ozpolat*

Volume 22, Issue 14, 2022

Published on: 15 April, 2022

Page: [2607 - 2618] Pages: 12

DOI: 10.2174/1871520622666220117123213

Price: $65

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer deaths in the US due to the lack of effective targeted therapeutics and extremely poor prognosis.

Objective: The study aims to investigate the role of miR-193b and related signaling mechanisms in PDAC cell proliferation, invasion, and tumor growth.

Methods: Using PDAC cell lines, we performed cell viability, colony formation, in vitro wound healing, and matrigel invasion assays following transfection with miR-193b mimic or control-miR. To identify potential downstream targets of miR-193b, we utilized miRNA-target prediction algorithms and investigated the regulation of eukaryotic elongation factor-2 kinase (eEF2K) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways and mediators of epithelial mesenchymal transition (EMT). The role of miR-193b in PDAC tumorigenesis was evaluated in in vivo tumor growth of Panc-1 xenograft model in nude mice.

Results: We found that miR-193b is under expressed in PDAC cells compared to corresponding normal pancreatic epithelial cells and demonstrated that ectopic expression of miR-193b reduced cell proliferation, migration, invasion, and EMT through downregulation of eEF2K signaling in PDAC cells. miR-193b expression led to increased expression of E-Cadherin and Claudin-1 while decreasing Snail and TCF8/ZEB1 expressions via eEF2K and MAPK/ERK axis. In vivo systemic injection of miR-193b using lipid-nanoparticles twice a week reduced tumor growth of Panc-1 xenografts and eEF2K expression in nude mice.

Conclusions: Our findings suggest that miR-193b expression suppresses PDAC cell proliferation, migration, invasion, and EMT through inhibition of eEF2K/MAPK-ERK oncogenic axis and that miR-193b-based RNA therapy might be an effective therapeutic strategy to control the growth of PDAC.

Keywords: Pancreatic cancer, miRNA, miR-193b, EMT, eEF2K, proliferation, metastasis.

« Previous Next »
Graphical Abstract

[1]
Lee, R.C.; Feinbaum, R.L.; Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell, 1993, 75(5), 843-854.
[http://dx.doi.org/10.1016/0092-8674(93)90529-Y] [PMID: 8252621]
[2]
Pritchard, C.C.; Cheng, H.H.; Tewari, M. MicroRNA profiling: Approaches and considerations. Nat. Rev. Genet., 2012, 13(5), 358-369.
[http://dx.doi.org/10.1038/nrg3198] [PMID: 22510765]
[3]
Bartel, D.P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 2004, 116(2), 281-297.
[http://dx.doi.org/10.1016/S0092-8674(04)00045-5] [PMID: 14744438]
[4]
Sethi, S.; Sethi, S.; Bluth, M.H. Clinical implication of microRNAs in molecular pathology: An update for 2018. Clin. Lab. Med., 2018, 38(2), 237-251.
[http://dx.doi.org/10.1016/j.cll.2018.02.003] [PMID: 29776629]
[5]
Garzon, R.; Calin, G.A.; Croce, C.M. MicroRNAs in cancer. Annu. Rev. Med., 2009, 60, 167-179.
[http://dx.doi.org/10.1146/annurev.med.59.053006.104707] [PMID: 19630570]
[6]
Rupaimoole, R.; Calin, G.A.; Lopez-Berestein, G.; Sood, A.K. miRNA deregulation in cancer cells and the tumor microenvironment. Cancer Discov., 2016, 6(3), 235-246.
[http://dx.doi.org/10.1158/2159-8290.CD-15-0893] [PMID: 26865249]
[7]
Spizzo, R.; Nicoloso, M.S.; Croce, C.M.; Calin, G.A. SnapShot: MicroRNAs in cancer. Cell, 2009, 137(3), 586-586.e1.
[http://dx.doi.org/10.1016/j.cell.2009.04.040] [PMID: 19410551]
[8]
Daoud, A.Z.; Mulholland, E.J.; Cole, G.; McCarthy, H.O. MicroRNAs in pancreatic cancer: Biomarkers, prognostic, and therapeutic modu-lators. BMC Cancer, 2019, 19(1), 1130.
[http://dx.doi.org/10.1186/s12885-019-6284-y] [PMID: 31752758]
[9]
Gurbuz, N.; Ozpolat, B. MicroRNA-based targeted therapeutics in pancreatic cancer. Anticancer Res., 2019, 39(2), 529-532.
[http://dx.doi.org/10.21873/anticanres.13144] [PMID: 30711926]
[10]
Mokhlis, H.A.; Bayraktar, R.; Kabil, N.N.; Caner, A.; Kahraman, N.; Rodriguez-Aguayo, C.; Zambalde, E.P.; Sheng, J.; Karagoz, K.; Kan-likilicer, P.; Abdel Aziz, A.A.H.; Abdelghany, T.M.; Ashour, A.A.; Wong, S.; Gatza, M.L.; Calin, G.A.; Lopez-Berestein, G.; Ozpolat, B. The modulatory role of microRNA-873 in the progression of KRAS-driven cancers. Mol. Ther. Nucleic Acids, 2019, 14, 301-317.
[http://dx.doi.org/10.1016/j.omtn.2018.11.019] [PMID: 30654191]
[11]
Rawat, M.; Kadian, K.; Gupta, Y.; Kumar, A.; Chain, P.S.G.; Kovbasnjuk, O.; Kumar, S.; Parasher, G. MicroRNA in pancreatic cancer: From biology to therapeutic potential. Genes (Basel), 2019, 10(10), 752.
[http://dx.doi.org/10.3390/genes10100752] [PMID: 31557962]
[12]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin., 2015, 65(1), 5-29.
[http://dx.doi.org/10.3322/caac.21254] [PMID: 25559415]
[13]
Caldas, C.; Kern, S.E. K-ras mutation and pancreatic adenocarcinoma. Int. J. Pancreatol., 1995, 18(1), 1-6.
[http://dx.doi.org/10.1007/BF02825415] [PMID: 7594765]
[14]
Wolfgang, C.L.; Herman, J.M.; Laheru, D.A.; Klein, A.P.; Erdek, M.A.; Fishman, E.K.; Hruban, R.H. Recent progress in pancreatic cancer. CA Cancer J. Clin., 2013, 63(5), 318-348.
[http://dx.doi.org/10.3322/caac.21190] [PMID: 23856911]
[15]
Gurbuz, N.; Ashour, A.A.; Alpay, S.N.; Ozpolat, B. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenici-ty and invasion of human pancreatic cancer cells. PLoS One, 2014, 9(9), e110067.
[http://dx.doi.org/10.1371/journal.pone.0110067] [PMID: 25268648]
[16]
Ashour, A.A.; Gurbuz, N.; Alpay, S.N.; Abdel-Aziz, A.A.; Mansour, A.M.; Huo, L.; Ozpolat, B. Elongation factor-2 kinase regulates TG2/β1 integrin/Src/uPAR pathway and epithelial-mesenchymal transition mediating pancreatic cancer cells invasion. J. Cell. Mol. Med., 2014, 18(11), 2235-2251.
[http://dx.doi.org/10.1111/jcmm.12361] [PMID: 25215932]
[17]
Karakas, D.; Ozpolat, B. Eukaryotic elongation factor-2 kinase (eEF2K) signaling in tumor and microenvironment as a novel molecular target. J. Mol. Med. (Berl.), 2020, 98(6), 775-787.
[http://dx.doi.org/10.1007/s00109-020-01917-8] [PMID: 32377852]
[18]
Xu, Y.F.; Hannafon, B.N.; Ding, W.Q. microRNA regulation of human pancreatic cancer stem cells. Stem Cell Investig., 2017, 4, 5.
[http://dx.doi.org/10.21037/sci.2017.01.01] [PMID: 28217707]
[19]
Träger, M.M.; Dhayat, S.A. Epigenetics of epithelial-to-mesenchymal transition in pancreatic carcinoma. Int. J. Cancer, 2017, 141(1), 24-32.
[http://dx.doi.org/10.1002/ijc.30626] [PMID: 28133736]
[20]
Jiang, J.H.; Liu, C.; Cheng, H.; Lu, Y.; Qin, Y.; Xu, Y.F.; Xu, J.; Long, J.; Liu, L.; Ni, Q.X.; Yu, X.J. Epithelial-mesenchymal transition in pancreatic cancer: Is it a clinically significant factor? Biochim. Biophys. Acta, 2015, 1855(1), 43-49.
[http://dx.doi.org/10.1016/j.bbcan.2014.11.004] [PMID: 25432020]
[21]
Passadouro, M.; Faneca, H. Managing pancreatic adenocarcinoma: A special focus in microrna gene therapy. Int. J. Mol. Sci., 2016, 17(5), 718.
[http://dx.doi.org/10.3390/ijms17050718] [PMID: 27187371]
[22]
Zhang, Y.; Li, M.; Wang, H.; Fisher, W.E.; Lin, P.H.; Yao, Q.; Chen, C. Profiling of 95 microRNAs in pancreatic cancer cell lines and sur-gical specimens by real-time PCR analysis. World J. Surg., 2009, 33(4), 698-709.
[http://dx.doi.org/10.1007/s00268-008-9833-0] [PMID: 19030927]
[23]
Kang, M.; Li, Y.; Zhu, S.; Zhang, S.; Guo, S.; Li, P. MicroRNA-193b acts as a tumor suppressor gene in human esophageal squamous cell carcinoma via target regulation of KRAS. Oncol. Lett., 2019, 17(4), 3965-3973.
[http://dx.doi.org/10.3892/ol.2019.10039] [PMID: 30881513]
[24]
Gao, J.; Ma, S.; Yang, F.; Chen, X.; Wang, W.; Zhang, J.; Li, Y.; Wang, T.; Shan, L. miR 193b exhibits mutual interaction with MYC, and suppresses growth and metastasis of osteosarcoma. Oncol. Rep., 2020, 44(1), 139-155.
[http://dx.doi.org/10.3892/or.2020.7601] [PMID: 32377743]
[25]
Karmakar, S.; Kaushik, G.; Nimmakayala, R.; Rachagani, S.; Ponnusamy, M.P.; Batra, S.K. MicroRNA regulation of K-Ras in pancreatic cancer and opportunities for therapeutic intervention. Semin. Cancer Biol., 2019, 54, 63-71.
[http://dx.doi.org/10.1016/j.semcancer.2017.11.020] [PMID: 29199014]
[26]
Jin, X.; Sun, Y.; Yang, H.; Li, J.; Yu, S.; Chang, X.; Lu, Z.; Chen, J. Deregulation of the MiR-193b-KRAS axis contributes to impaired cell growth in pancreatic cancer. PLoS One, 2015, 10(4), e0125515.
[http://dx.doi.org/10.1371/journal.pone.0125515] [PMID: 25905463]
[27]
Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 1976, 72, 248-254.
[http://dx.doi.org/10.1016/0003-2697(76)90527-3] [PMID: 942051]
[28]
Hamurcu, Z.; Ashour, A.; Kahraman, N.; Ozpolat, B. FOXM1 regulates expression of eukaryotic elongation factor 2 kinase and promotes proliferation, invasion and tumorgenesis of human triple negative breast cancer cells. Oncotarget, 2016, 7(13), 16619-16635.
[http://dx.doi.org/10.18632/oncotarget.7672] [PMID: 26918606]
[29]
Bayraktar, R.; Ivan, C.; Bayraktar, E.; Kanlikilicer, P.; Kabil, N.N.; Kahraman, N.; Mokhlis, H.A.; Karakas, D.; Rodriguez-Aguayo, C.; Arslan, A.; Sheng, J.; Wong, S.; Lopez-Berestein, G.; Calin, G.A.; Ozpolat, B. Dual suppressive effect of miR-34a on the FOXM1/eEF2-kinase axis regulates triple-negative breast cancer growth and invasion. Clin. Cancer Res., 2018, 24(17), 4225-4241.
[http://dx.doi.org/10.1158/1078-0432.CCR-17-1959] [PMID: 29748184]
[30]
Bayraktar, R.; Pichler, M.; Kanlikilicer, P.; Ivan, C.; Bayraktar, E.; Kahraman, N.; Aslan, B.; Oguztuzun, S.; Ulasli, M.; Arslan, A.; Calin, G.; Lopez-Berestein, G.; Ozpolat, B. MicroRNA 603 acts as a tumor suppressor and inhibits triple-negative breast cancer tumorigenesis by targeting elongation factor 2 kinase. Oncotarget, 2017, 8(7), 11641-11658.
[http://dx.doi.org/10.18632/oncotarget.14264] [PMID: 28036267]
[31]
Gorur, A.; Bayraktar, R.; Ivan, C.; Mokhlis, H.A.; Bayraktar, E.; Kahraman, N.; Karakas, D.; Karamil, S.; Kabil, N.N.; Kanlikilicer, P.; Aslan, B.; Tamer, L.; Wang, Z.; Cristini, V.; Lopez-Berestein, G.; Calin, G.; Ozpolat, B. ncRNA therapy with miRNA-22-3p suppresses the growth of triple-negative breast cancer. Mol. Ther. Nucleic Acids, 2021, 23, 930-943.
[http://dx.doi.org/10.1016/j.omtn.2021.01.016] [PMID: 33614241]
[32]
Ashour, A.A.; Abdel-Aziz, A.A.; Mansour, A.M.; Alpay, S.N.; Huo, L.; Ozpolat, B. Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells. Apoptosis, 2014, 19(1), 241-258.
[http://dx.doi.org/10.1007/s10495-013-0927-2] [PMID: 24193916]
[33]
Yamada, S.; Fuchs, B.C.; Fujii, T.; Shimoyama, Y.; Sugimoto, H.; Nomoto, S.; Takeda, S.; Tanabe, K.K.; Kodera, Y.; Nakao, A. Epithelial-to-mesenchymal transition predicts prognosis of pancreatic cancer. Surgery, 2013, 154(5), 946-954.
[http://dx.doi.org/10.1016/j.surg.2013.05.004] [PMID: 24075276]
[34]
Olea-Flores, M.; Zuñiga-Eulogio, M.D.; Mendoza-Catalán, M.A.; Rodríguez-Ruiz, H.A.; Castañeda-Saucedo, E.; Ortuño-Pineda, C. Pa-dilla-Benavides, T.; Navarro-Tito, N. Extracellular-signal regulated kinase: A central molecule driving epithelial-mesenchymal transition in cancer. Int. J. Mol. Sci., 2019, 20(12), 2885.
[http://dx.doi.org/10.3390/ijms20122885] [PMID: 31200510]
[35]
Parmer, T.G.; Ward, M.D.; Yurkow, E.J.; Vyas, V.H.; Kearney, T.J.; Hait, W.N. Activity and regulation by growth factors of calmodulin-dependent protein kinase III (elongation factor 2-kinase) in human breast cancer. Br. J. Cancer, 1999, 79(1), 59-64.
[http://dx.doi.org/10.1038/sj.bjc.6690012] [PMID: 10408694]
[36]
Bircan, H.A.; Gurbuz, N.; Pataer, A.; Caner, A.; Kahraman, N.; Bayraktar, E.; Bayraktar, R.; Erdogan, M.A.; Kabil, N.; Ozpolat, B. Elonga-tion factor-2 kinase (eEF-2K) expression is associated with poor patient survival and promotes proliferation, invasion and tumor growth of lung cancer. Lung Cancer, 2018, 124, 31-39.
[http://dx.doi.org/10.1016/j.lungcan.2018.07.027] [PMID: 30268477]
[37]
Le Large, T.Y.; Meijer, L.L.; Prado, M.M.; Kazemier, G.; Frampton, A.E.; Giovannetti, E. Circulating microRNAs as diagnostic biomarkers for pancreatic cancer. Expert Rev. Mol. Diagn., 2015, 15(12), 1525-1529.
[http://dx.doi.org/10.1586/14737159.2015.1112273] [PMID: 26567751]
[38]
Szafranska, A.E.; Davison, T.S.; John, J.; Cannon, T.; Sipos, B.; Maghnouj, A.; Labourier, E.; Hahn, S.A. MicroRNA expression altera-tions are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene, 2007, 26(30), 4442-4452.
[http://dx.doi.org/10.1038/sj.onc.1210228] [PMID: 17237814]
[39]
Yonemori, K.; Kurahara, H.; Maemura, K.; Natsugoe, S. MicroRNA in pancreatic cancer. J. Hum. Genet., 2017, 62(1), 33-40.
[http://dx.doi.org/10.1038/jhg.2016.59] [PMID: 27251005]
[40]
Yang, Z.; He, M.; Wang, K.; Sun, G.; Tang, L.; Xu, Z. Tumor suppressive microRNA-193b promotes breast cancer progression via target-ing DNAJC13 and RAB22A. Int. J. Clin. Exp. Pathol., 2014, 7(11), 7563-7570.
[PMID: 25550792]
[41]
Hu, S.; Cao, M.; He, Y.; Zhang, G.; Liu, Y.; Du, Y.; Yang, C.; Gao, F. CD44v6 targeted by miR-193b-5p in the coding region modulates the migration and invasion of breast cancer cells. J. Cancer, 2020, 11(1), 260-271.
[http://dx.doi.org/10.7150/jca.35067] [PMID: 31892992]
[42]
Hulin, J.A.; Tommasi, S.; Elliot, D.; Hu, D.G.; Lewis, B.C.; Mangoni, A.A. MiR-193b regulates breast cancer cell migration and vasculo-genic mimicry by targeting dimethylarginine dimethylaminohydrolase 1. Sci. Rep., 2017, 7(1), 13996.
[http://dx.doi.org/10.1038/s41598-017-14454-1] [PMID: 29070803]
[43]
Long, J.; Ji, Z.; Jiang, K.; Wang, Z.; Meng, G. miR-193b Modulates Resistance to doxorubicin in human breast cancer cells by downregu-lating MCL-1. BioMed Res. Int., 2015, 2015, 373574.
[http://dx.doi.org/10.1155/2015/373574] [PMID: 26526790]
[44]
Li, X.F.; Yan, P.J.; Shao, Z.M. Downregulation of miR-193b contributes to enhance urokinase-type plasminogen activator (uPA) expres-sion and tumor progression and invasion in human breast cancer. Oncogene, 2009, 28(44), 3937-3948.
[http://dx.doi.org/10.1038/onc.2009.245] [PMID: 19701247]
[45]
Mazzu, Y.Z.; Yoshikawa, Y.; Nandakumar, S.; Chakraborty, G.; Armenia, J.; Jehane, L.E.; Lee, G.M.; Kantoff, P.W. Methylation-associated miR-193b silencing activates master drivers of aggressive prostate cancer. Mol. Oncol., 2019, 13(9), 1944-1958.
[http://dx.doi.org/10.1002/1878-0261.12536] [PMID: 31225930]
[46]
Kaukoniemi, K.M.; Rauhala, H.E.; Scaravilli, M.; Latonen, L.; Annala, M.; Vessella, R.L.; Nykter, M.; Tammela, T.L.; Visakorpi, T. Epi-genetically altered miR-193b targets cyclin D1 in prostate cancer. Cancer Med., 2015, 4(9), 1417-1425.
[http://dx.doi.org/10.1002/cam4.486] [PMID: 26129688]
[47]
Chen, J.; Deng, T.; Li, X.; Cai, W. MiR-193b inhibits the growth and metastasis of renal cell carcinoma by targeting IGF1R. Artif. Cells Nanomed. Biotechnol., 2019, 47(1), 2058-2064.
[http://dx.doi.org/10.1080/21691401.2019.1620251] [PMID: 31126198]
[48]
Nakano, H.; Yamada, Y.; Miyazawa, T.; Yoshida, T. Gain-of-function microRNA screens identify miR-193a regulating proliferation and apoptosis in epithelial ovarian cancer cells. Int. J. Oncol., 2013, 42(6), 1875-1882.
[http://dx.doi.org/10.3892/ijo.2013.1896] [PMID: 23588298]
[49]
Li, J.; Kong, F.; Wu, K.; Song, K.; He, J.; Sun, W. miR-193b directly targets STMN1 and uPA genes and suppresses tumor growth and metastasis in pancreatic cancer. Mol. Med. Rep., 2014, 10(5), 2613-2620.
[http://dx.doi.org/10.3892/mmr.2014.2558] [PMID: 25215905]
[50]
Akamatsu, M.; Makino, N.; Ikeda, Y.; Matsuda, A.; Ito, M.; Kakizaki, Y.; Saito, Y.; Ishizawa, T.; Kobayashi, T.; Furukawa, T.; Ueno, Y. Specific MAPK-associated microRNAs in serum differentiate pancreatic cancer from autoimmune pancreatitis. PLoS One, 2016, 11(7), e0158669.
[http://dx.doi.org/10.1371/journal.pone.0158669] [PMID: 27380024]
[51]
Ikeda, Y.; Tanji, E.; Makino, N.; Kawata, S.; Furukawa, T. MicroRNAs associated with mitogen-activated protein kinase in human pancre-atic cancer. Mol. Cancer Res., 2012, 10(2), 259-269.
[http://dx.doi.org/10.1158/1541-7786.MCR-11-0035] [PMID: 22188669]
[52]
Bader, A.G. miR-34 - a microRNA replacement therapy is headed to the clinic. Front. Genet., 2012, 3, 120.
[http://dx.doi.org/10.3389/fgene.2012.00120] [PMID: 22783274]
[53]
Seto, A.G.; Beatty, X.; Lynch, J.M.; Hermreck, M.; Tetzlaff, M.; Duvic, M.; Jackson, A.L. Cobomarsen, an oligonucleotide inhibitor of miR-155, co-ordinately regulates multiple survival pathways to reduce cellular proliferation and survival in cutaneous T-cell lymphoma. Br. J. Haematol., 2018, 183(3), 428-444.
[http://dx.doi.org/10.1111/bjh.15547] [PMID: 30125933]

Rights & Permissions Print Cite
Article Metrics
30
1
© 2024 Bentham Science Publishers | Privacy Policy