MicroRNA-497 suppresses angiogenesis by targeting vascular endothelial growth factor A through the PI3K/AKT and MAPK/ERK pathways in ovarian cancer

Wang,Wei; Ren,Fang; Wu,Qinghua; Jiang,Dazhi; Li,Hongjun; Shi,Huirong

doi:10.3892/or.2014.3439

MicroRNA-497 suppresses angiogenesis by targeting vascular endothelial growth factor A through the PI3K/AKT and MAPK/ERK pathways in ovarian cancer

Authors:
- Wei Wang
- Fang Ren
- Qinghua Wu
- Dazhi Jiang
- Hongjun Li
- Huirong Shi
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Affiliations: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China, Department of Nuclear Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Published online on: August 22, 2014 https://doi.org/10.3892/or.2014.3439
Pages: 2127-2133

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Abstract

MicroRNAs (miRNAs) have been shown to play an important role in diverse biological processes and cancer progression. The objective of the present study was to investigate the role of miR-497 in ovarian cancer angiogenesis. We found that miR-497 expression was downregulated in human ovarian cancer tissues, and the low miR-497 expression was significantly associated with increased angiogenesis. Functionally, exogenous expression of miR-497 suppressed the ability of ovarian cancer cells to promote capillary tube formation of endothelial cells. We further disclosed that miR-497 exerted its function of anti-angiogenesis by suppressing VEGFA expression in ovarian cancer cells and, in turn, impairing the VEGFR2-mediated PI3K/AKT and MAPK/ERK pathways. Our findings suggest that downregulation of miR-497 may contribute to angiogenesis in ovarian cancer. miR-497 may be a promising candidate target for prevention and treatment of ovarian cancer.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar
2	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
3	Weis SM and Cheresh DA: Tumor angiogenesis: molecular pathways and therapeutic targets. Nat Med. 17:1359–1370. 2011. View Article : Google Scholar : PubMed/NCBI
4	Carmeliet P and Jain RK: Molecular mechanisms and clinical applications of angiogenesis. Nature. 473:298–307. 2011. View Article : Google Scholar : PubMed/NCBI
5	Croce CM: miRNAs in the spotlight: understanding cancer gene dependency. Nat Med. 17:935–936. 2011. View Article : Google Scholar : PubMed/NCBI
6	Su Y, Li X, Ji W, et al: Small molecule with big role: microRNAs in cancer metastatic microenvironments. Cancer Lett. 344:147–156. 2014. View Article : Google Scholar : PubMed/NCBI
7	Eilken HM and Adams RH: Turning on the angiogenic microswitch. Nat Med. 16:853–854. 2010. View Article : Google Scholar : PubMed/NCBI
8	Conteduca V, Kopf B, Burgio SL, Bianchi E, Amadori D and De Giorgi U: The emerging role of anti-angiogenic therapy in ovarian cancer (Review). Int J Oncol. 44:1417–1424. 2014.PubMed/NCBI
9	Finnerty JR, Wang WX, Hébert SS, Wilfred BR, Mao G and Nelson PT: The miR-15/107 group of microRNA genes: evolutionary biology, cellular functions, and roles in human diseases. J Mol Biol. 402:491–509. 2010. View Article : Google Scholar : PubMed/NCBI
10	Flavin RJ, Smyth PC, Laios A, et al: Potentially important microRNA cluster on chromosome 17p13.1 in primary peritoneal carcinoma. Mod Pathol. 22:197–205. 2009. View Article : Google Scholar : PubMed/NCBI
11	Zhang L, Huang J, Yang N, et al: microRNAs exhibit high frequency genomic alterations in human cancer. Proc Natl Acad Sci USA. 103:9136–9141. 2006. View Article : Google Scholar : PubMed/NCBI
12	Tahiri A, Leivonen SK, Lüders T, et al: Deregulation of cancer-related miRNAs is a common event in both benign and malignant human breast tumors. Carcinogenesis. 35:76–85. 2014. View Article : Google Scholar : PubMed/NCBI
13	Creevey L, Ryan J, Harvey H, et al: MicroRNA-497 increases apoptosis in MYCN amplified neuroblastoma cells by targeting the key cell cycle regulator WEE1. Mol Cancer. 12:232013.PubMed/NCBI
14	Zhao WY, Wang Y, An ZJ, et al: Downregulation of miR-497 promotes tumor growth and angiogenesis by targeting HDGF in non-small cell lung cancer. Biochem Biophys Res Commun. 435:466–471. 2013. View Article : Google Scholar : PubMed/NCBI
15	Li D, Zhao Y, Liu C, et al: Analysis of miR-195 and miR-497 expression, regulation and role in breast cancer. Clin Cancer Res. 17:1722–1730. 2011. View Article : Google Scholar : PubMed/NCBI
16	Guo ST, Jiang CC, Wang GP, et al: MicroRNA-497 targets insulin-like growth factor 1 receptor and has a tumour suppressive role in human colorectal cancer. Oncogene. 32:1910–1920. 2013. View Article : Google Scholar : PubMed/NCBI
17	Kim YW, Kim EY, Jeon D, et al: Differential microRNA expression signatures and cell type-specific association with Taxol resistance in ovarian cancer cells. Drug Des Devel Ther. 8:293–314. 2014.PubMed/NCBI
18	Lajer CB, Garnæs E, Friis-Hansen L, et al: The role of miRNAs in human papilloma virus (HPV)-associated cancers: bridging between HPV-related head and neck cancer and cervical cancer. Br J Cancer. 106:1526–1534. 2012. View Article : Google Scholar : PubMed/NCBI
19	Caramuta S, Lee L, Ozata DM, et al: Clinical and functional impact of TARBP2 over-expression in adrenocortical carcinoma. Endocr Relat Cancer. 20:551–564. 2013. View Article : Google Scholar : PubMed/NCBI
20	Lionetti M, Musto P, Di Martino MT, et al: Biological and clinical relevance of miRNA expression signatures in primary plasma cell leukemia. Clin Cancer Res. 19:3130–3142. 2013. View Article : Google Scholar : PubMed/NCBI
21	Claesson-Welsh L and Welsh M: VEGFA and tumour angiogenesis. J Intern Med. 273:114–127. 2013. View Article : Google Scholar : PubMed/NCBI
22	Welti J, Loges S, Dimmeler S and Carmeliet P: Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer. J Clin Invest. 123:3190–3200. 2013. View Article : Google Scholar : PubMed/NCBI
23	Larsen AK, Ouaret D, El Ouadrani K and Petitprez A: Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis. Pharmacol Ther. 131:80–90. 2011. View Article : Google Scholar : PubMed/NCBI
24	Anand S and Cheresh DA: Emerging role of micro-RNAs in the regulation of angiogenesis. Genes Cancer. 2:1134–1138. 2011. View Article : Google Scholar : PubMed/NCBI
25	Zhou B, Ma R, Si W, et al: MicroRNA-503 targets FGF2 and VEGFA and inhibits tumor angiogenesis and growth. Cancer Lett. 333:159–169. 2013. View Article : Google Scholar : PubMed/NCBI
26	Sun CY, She XM, Qin Y, et al: miR-15a and miR-16 affect the angiogenesis of multiple myeloma by targeting VEGF. Carcinogenesis. 34:426–435. 2013. View Article : Google Scholar : PubMed/NCBI
27	Zheng X, Chopp M, Lu Y, Buller B and Jiang F: MiR-15b and miR-152 reduce glioma cell invasion and angiogenesis via NRP-2 and MMP-3. Cancer Lett. 329:146–154. 2013. View Article : Google Scholar : PubMed/NCBI
28	Xu Q, Liu LZ, Qian X, et al: MiR-145 directly targets p70S6K1 in cancer cells to inhibit tumor growth and angiogenesis. Nucleic Acids Res. 40:761–774. 2012. View Article : Google Scholar : PubMed/NCBI
29	Zhang H, Pu J, Qi T, et al: MicroRNA-145 inhibits the growth, invasion, metastasis and angiogenesis of neuroblastoma cells through targeting hypoxia-inducible factor 2 alpha. Oncogene. 33:387–397. 2014. View Article : Google Scholar : PubMed/NCBI
30	Yin R, Bao W, Xing Y, Xi T and Gou S: MiR-19b-1 inhibits angiogenesis by blocking cell cycle progression of endothelial cells. Biochem Biophys Res Commun. 417:771–776. 2012. View Article : Google Scholar : PubMed/NCBI
31	Saharinen P, Eklund L, Pulkki K, Bono P and Alitalo K: VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol Med. 17:347–362. 2011. View Article : Google Scholar : PubMed/NCBI
32	Eng L, Azad AK, Habbous S, et al: Vascular endothelial growth factor pathway polymorphisms as prognostic and pharmacogenetic factors in cancer: a systematic review and meta-analysis. Clin Cancer Res. 18:4526–4537. 2012. View Article : Google Scholar
33	Yu L, Deng L, Li J, Zhang Y and Hu L: The prognostic value of vascular endothelial growth factor in ovarian cancer: a systematic review and meta-analysis. Gynecol Oncol. 128:391–396. 2013. View Article : Google Scholar : PubMed/NCBI
34	Ferrara N: Pathways mediating VEGF-independent tumor angiogenesis. Cytokine Growth Factor Rev. 21:21–26. 2010. View Article : Google Scholar : PubMed/NCBI
35	Xu Q, Jiang Y, Yin Y, et al: A regulatory circuit of miR-148a/152 and DNMT1 in modulating cell transformation and tumor angiogenesis through IGF-IR and IRS1. J Mol Cell Biol. 5:3–13. 2013. View Article : Google Scholar : PubMed/NCBI
36	DA Silva ND Jr, Fernandes T, Soci UP, Monteiro AW, Phillips MI and DE Oliveira EM: Swimming training in rats increases cardiac microRNA-126 expression and angiogenesis. Med Sci Sports Exerc. 44:1453–1462. 2012.PubMed/NCBI
37	Bao L, Yan Y, Xu C, et al: MicroRNA-21 suppresses PTEN and hSulf-1 expression and promotes hepatocellular carcinoma progression through AKT/ERK pathways. Cancer Lett. 337:226–236. 2013. View Article : Google Scholar : PubMed/NCBI
38	Chan JK, Kiet TK, Blansit K, et al: MiR-378 as a biomarker for response to anti-angiogenic treatment in ovarian cancer. Gynecol Oncol. 133:568–574. 2014. View Article : Google Scholar
39	Pecot CV, Rupaimoole R, Yang D, et al: Tumour angiogenesis regulation by the miR-200 family. Nat Commun. 4:24272013. View Article : Google Scholar : PubMed/NCBI
40	Vecchione A, Belletti B, Lovat F, et al: A microRNA signature defines chemoresistance in ovarian cancer through modulation of angiogenesis. Proc Natl Acad Sci USA. 110:9845–9850. 2013. View Article : Google Scholar : PubMed/NCBI
41	Lai Y, Zhang X, Zhang Z, et al: The microRNA-27a: ZBTB10-specificity protein pathway is involved in follicle stimulating hormone-induced VEGF, Cox2 and survivin expression in ovarian epithelial cancer cells. Int J Oncol. 42:776–784. 2013.