Abstract
MicroRNAs (miRNAs) play critical roles in the development and progression of ovarian cancer. We found that miR-212 was significantly downregulated in serum and tissues from epithelial ovarian cancer (EOC) patients. Overexpression of miR-212 in ovarian cancer cells inhibited cell proliferation, migration, and invasion. Luciferase reporter assay confirmed HBEGF as a direct target of miR-212. Overexpression of miR-212 decreased HBEGF expression at both the protein and messenger RNA (mRNA) levels. Knockdown of HBEGF expression in SKOV3 cell line significantly inhibited cell growth, migration, and invasion. HBEGF mRNA level was upregulated in EOC tissues and inversely correlated with miR-212 expression in tissues. Upregulation of HBEGF could attenuate the effect induced by miR-212. These findings indicate that miR-212 displays a tumor-suppressive effect in human ovarian cancer. And miR-212 suppresses cell proliferation, migration, and invasion by targeting the HBEGF transcript, highlighting the therapeutic potential of miR-212 and HBEGF in epithelial ovarian cancer treatment.
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References
Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.
Marcus CS, Maxwell GL, Darcy KM, et al. Current approaches and challenges in managing and monitoring treatment response in ovarian cancer. J Cancer. 2014;5(1):25–30.
Shukla GC, Singh J, Barik S. MicroRNAs: processing, maturation, target recognition and regulatory functions. Mol Cell Pharmacol. 2011;3:83–92.
Xi JJ. MicroRNAs in cancer. Cancer Treat Res. 2013;158:119–37.
Liang X, Zeng J, Wang L, Fang M, Wang Q, Zhao M, et al. Histone demethylase retinoblastoma binding protein 2 is overexpressed in hepatocellular carcinoma and negatively regulated by hsa-miR-212. PLoS ONE. 2013;8:e69784.
Jiping Z, Ming F, Lixiang W, Xiuming L, Yuqun S, Han Y, et al. MicroRNA-212 inhibits proliferation of gastric cancer by directly repressing retinoblastoma binding protein 2. J Cell Biochem. 2013;114:2666–72.
Meng X, Wu J, Pan C, Wang H, Ying X, Zhou Y, et al. Genetic and epigenetic down-regulation of microRNA-212 promotes colorectal tumor metastasis via dysregulation of MnSOD. Gastroenterology. 2013;145(2):426–36.
Sankaranarayanan R, Ferlay J. Worldwide burden of gynaecological cancer: the size of the problem. Best Pract Res Clin Obstet Gynaecol. 2006;20:207–25.
Li Y, Zhang D, Chen C, et al. MicroRNA-212 displays tumor-promoting properties in non-small cell lung cancer cells and targets the hedgehog pathway receptor PTCH1. Mol Biol Cell. 2012;23:1423–34.
Ma C, Nong K, Wu B, et al. miR-212 promotes pancreatic cancer cell growth and invasion by targeting the hedgehog signaling pathway receptor patched-1. J Exp Clin Cancer Res. 2014;33:54.
Higashiyama S, Abraham JA, Miller J, Fiddes JC, Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science. 1991;251:936–9.
Raab G, Higashiyama S, Hetelekidis S, et al. Biosynthesis and processing by phorbol ester of the cells surface-associated precursor form of heparin-binding EGF-like growth factor. Biochem Biophys Res Commun. 1994;204:592–7.
Higashiyama S, Lau K, Besner GE, et al. Structure of heparin-binding EGF-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein. J Biol Chem. 1992;267:6205–12.
Higashiyama S, Abraham JA, Klagsbrun M. Heparin-binding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate. J Cell Biol. 1993;122:933–40.
Marikovsky M, Breuing K, Liu PY, et al. Appearance of heparin-binding EGF-like growth factor in wound fluid as a response to injury. Proc Natl Acad Sci U S A. 1993;90:3889–93.
Hashimoto K, Higashiyama S, Asada H, et al. Heparin-binding epidermal growth factor-like growth factor is an autocrine growth factor for human keratinocytes. J Biol Chem. 1994;269:20060–6.
Peoples GE, Blotnick S, Takahashi K, et al. T lymphocytes that infiltrate tumors and atherosclerotic plaques produce heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor: a potential pathologic role. Proc Natl Acad Sci U S A. 1995;92:6547–51.
Higashiyama S, Iwamoto R, Goishi K, et al. The membrane protein CD9/DRAP 27 potentiates the juxtacrine growth factor activity of the membrane-anchored heparin-binding EGF-like growth factor. J Cell Biol. 1995;128:929–38.
Iwamoto R, Higashiyama S, Mitamura T, et al. Heparin-binding EGF-like growth factor, which acts as the diphtheria toxin receptor, forms a complex with membrane protein DRAP27/CD9, which up-regulates functional receptors and diphtheria toxin sensitivity. EMBO J. 1994;13:2322–30.
Yotsumoto F, Yagi H, Suzuki SO, et al. Validation of HB-EGF and amphiregulin as targets for human cancer therapy. Biochem Biophys Res Commun. 2008;365(3):555–61.
Miyamoto S, Hirata M, Yamazaki A, et al. Heparin-binding EGF-like growth factor is a promising target for ovarian cancer therapy. Cancer Res. 2004;64:5720–7.
Ohnishi Y, Inoue H, Furukawa M, et al. Heparin-binding epidermal growth factor-like growth factor is a potent regulator of invasion activity in oral squamous cell carcinoma. Oncol Rep. 2012;27:954–8.
Haugen DR, Akslen LA, Varhaug JE, et al. Expression of c-erbB-3 and c-erbB-4 proteins in papillary thyroid carcinomas. Cancer Res. 1996;56:1184–8.
Chandler LA, Sosnowski BA, McDonald JR, et al. Targeting tumor cells via EGF receptors: selective toxicity of an HBEGF-toxin fusion protein. Int J Cancer. 1998;78:106–11.
Ota I, Higashiyama S, Masui T, et al. Heparin-binding EGF-like growth factor enhances the activity of invasion and metastasis in thyroid cancer cells. Oncol Rep. 2013;30:1593–600.
Zhou Z N, Sharma V P, Beaty B T, et al. Autocrine HBEGF expression promotes breast cancer intravasation, metastasis and macrophage-independent invasion in vivo. Oncogene, 2013.
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This work was supported by the Education department of Henan province science and technology research projects (12A320035). We thank Yan-mei Ma for generally providing the SKOV3 cell line.
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Wei, Lq., Liang, Ht., Qin, Dc. et al. MiR-212 exerts suppressive effect on SKOV3 ovarian cancer cells through targeting HBEGF. Tumor Biol. 35, 12427–12434 (2014). https://doi.org/10.1007/s13277-014-2560-2
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DOI: https://doi.org/10.1007/s13277-014-2560-2