Oleuropein inhibits pancreatic cancer through miR-190b-5p induction
Abstract
Background: Pancreatic cancer has the highest mortality rate of all major cancers. Till now, surgical resection is considered the only potentially curative therapy. The aim of this study was to study oleuropein (Ole) as an alternative treatment for pancreatic cancer.
Methods: First, we determined the tumor-inhibitory effect of Ole in pancreatic cancer cell lines and the KPC mouse model. Second, we employed microarray and real-time polymerase chain reaction to identify microRNAs (miRNA) regulated by Ole in pancreatic cancer. Third, we mapped out the downstream target of the miRNA candidate by luciferase assay and western blotting. Finally, we measured the tissue expression of the miRNA candidate in clinical samples. Both in vitro and in vivo studies supported Ole treatment suppressed pancreatic cancer.
Results: We profiled miRNAs changes induced by Ole and identified miR-190b-5p as a novel functional player in Ole-mediated pancreatic cancer suppression. Further on, we reported that TCF4 in Wnt signaling was a direct target of miR-190b-5p. The suppression of Wnt signaling by miR-190b-5p was attributed to Ole-induced tumor inhibition in a pancreatic cancer model. Finally, we showed that miR-190b-5p was downregulated in human clinical cancer samples.
Conclusion: In summary, we discovered that Ole carried anti-pancreatic cancer function. MiR-190b-5p induced by Ole was a potential therapeutic target.
Downloads
References
Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet 2004; 363(9414): 1049–57. doi: 10.1016/S0140-6736(04)15841-8
Hidalgo M. Pancreatic cancer. N Engl J Med 2010; 362(17): 1605–17. doi: 10.1056/NEJMra0901557
Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321(5897): 1801–6. doi: 10.1126/science.1164368
Waddell N, Pajic M, Patch AM, Chang DK, Kassahn KS, Bailey P, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015; 518(7540): 495–501. doi: 10.1038/nature14169
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369(18): 1691–703. doi: 10.1056/NEJMoa1304369
Hidalgo M, Cascinu S, Kleeff J, Labianca R, Lohr JM, Neoptolemos J, et al. Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatology 2015; 15(1): 8–18. doi: 10.1016/j.pan.2014.10.001
Barbaro B, Toietta G, Maggio R, Arciello M, Tarocchi M, Galli A, et al. Effects of the olive-derived polyphenol oleuropein on human health. Int J Mol Sci 2014; 15(10): 18508–24. doi: 10.3390/ijms151018508
Omar SH. Oleuropein in olive and its pharmacological effects. Sci Pharm 2010; 78(2): 133–54. doi: 10.3797/scipharm.0912-18
Carrera-González MP, Ramírez-Expósito MJ, Mayas MD, Martínez-Martos JM. Protective role of oleuropein and its metabolite hydroxytyrosol on cancer. Trends Food Sci Technol 2013; 31(2): 92–9. doi: 10.1016/j.tifs.2013.03.003
Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005; 7(5): 469–83. doi: 10.1016/j.ccr.2005.04.023
Pramanik D, Campbell NR, Karikari C, Chivukula R, Kent OA, Mendell JT, et al. Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice. Mol Cancer Ther 2011; 10(8): 1470–80. doi: 10.1158/1535-7163.MCT-11-0152
Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. eLife 2015; 4: e05005. doi: 10.7554/eLife.05005
Morris JPt, Wang SC, Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer 2010; 10(10): 683–95. doi: 10.1038/nrc2899
Cardeno A, Sanchez-Hidalgo M, Rosillo MA, Alarcon de la Lastra C. Oleuropein, a secoiridoid derived from olive tree, inhibits the proliferation of human colorectal cancer cell through downregulation of HIF-1alpha. Nutr Cancer 2013; 65(1): 147–56. doi: 10.1080/01635581.2013.741758
Giner E, Recio MC, Rios JL, Cerda-Nicolas JM, Giner RM. Chemopreventive effect of oleuropein in colitis-associated colorectal cancer in c57bl/6 mice. Mol Nutr Food Res 2016; 60(2): 242–55. doi: 10.1002/mnfr.201500605
Hassan ZK, Elamin MH, Omer SA, Daghestani MH, Al-Olayan ES, Elobeid MA, et al. Oleuropein induces apoptosis via the p53 pathway in breast cancer cells. Asian Pac J Cancer Prev 2014; 14(11): 6739–42. doi: 10.7314/APJCP.2013.14.11.6739
Goldsmith CD, Bond DR, Jankowski H, Weidenhofer J, Stathopoulos CE, Roach PD, et al. The olive biophenols oleuropein and hydroxytyrosol selectively reduce proliferation, influence the cell cycle, and induce apoptosis in pancreatic cancer cells. Int J Mol Sci 2018; 19(7). doi: 10.3390/ijms19071937
Zhou B, Sun C, Hu X, Zhan H, Zou H, Feng Y, et al. MicroRNA-195 Suppresses the progression of pancreatic cancer by targeting DCLK1. Cell Physiol Biochem 2017; 44(5): 1867–81. doi: 10.1159/000485876
Wang S, Ji J, Song J, Li X, Han S, Lian W, et al. MicroRNA-182 promotes pancreatic cancer cell proliferation and migration by targeting beta-TrCP2. Acta Biochim Biophys Sin 2016; 48(12): 1085–93. doi: 10.1093/abbs/gmw105
Kang M, Xia P, Hou T, Qi Z, Liao S, Yang X. MicroRNA-190b inhibits tumor cell proliferation and induces apoptosis by regulating Bcl-2 in U2OS osteosarcoma cells. Pharmazie 2017; 72(5): 279–82. doi: 10.1691/ph.2017.6921
Wang C, Qiao C. MicroRNA-190b confers radio-sensitivity through negative regulation of Bcl-2 in gastric cancer cells. Biotechnol Lett 2017; 39(4): 485–90. doi: 10.1007/s10529-016-2273-2
Xing Y, Cui D, Wang S, Wang P, Xing X, Li H. Oleuropein represses the radiation resistance of ovarian cancer by inhibiting hypoxia and microRNA-299-targetted heparanase expression. Food Funct 2017; 8(8): 2857–64. doi: 10.1039/c7fo00552k
Hung TM, Ho CM, Liu YC, Lee JL, Liao YR, Wu YM, et al. Up-regulation of microRNA-190b plays a role for decreased IGF-1 that induces insulin resistance in human hepatocellular carcinoma. PLoS One 2014; 9(2): e89446. doi: 10.1371/journal.pone.0089446
Cizeron-Clairac G, Lallemand F, Vacher S, Lidereau R, Bieche I, Callens C. MiR-190b, the highest up-regulated miRNA in ERalpha-positive compared to ERalpha-negative breast tumors, a new biomarker in breast cancers? BMC Cancer 2015; 15: 499. doi: 10.1186/s12885-015-1505-5
Polakis P. Wnt signaling and cancer. Genes Dev 2000; 14(15): 1837–51. doi: 10.1101/gad.14.15.1837
Wong HH, Lemoine NR. Pancreatic cancer: molecular pathogenesis and new therapeutic targets. Nat Rev Gastroenterol Hepatol 2009; 6(7): 412–22. doi: 10.1038/nrgastro.2009.89
Copyright (c) 2022 Qian Xu, Xiaobing Huang, Ningzi Wu, Peifeng Hou
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors retain full copyright to their individual works, and publishing rights without restrictions.
In accordance with the Budapest Open Access Initiative, articles published in STEMedicine are freely available "on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited."
Except where otherwise noted, all content on this website is licensed under a Creative Commons Attribution 4.0 License. This license allows for commercial and non-commercial redistribution as well as modifications of the work as long as attribution is given to the authors and STEMedicine as the original publication source, and a link to the article on the STEMedicine website is provided.
