MicroRNA‑576‑3p inhibits the migration and proangiogenic abilities of hypoxia‑treated glioma cells through hypoxia‑inducible factor‑1α

Hu,Qing; Liu,Feng; Yan,Tengfeng; Wu,Miaojing; Ye,Minhua; Shi,Guangyao; Lv,Shigang; Zhu,Xingen

doi:10.3892/ijmm.2019.4157

MicroRNA‑576‑3p inhibits the migration and proangiogenic abilities of hypoxia‑treated glioma cells through hypoxia‑inducible factor‑1α

Authors:
- Qing Hu
- Feng Liu
- Tengfeng Yan
- Miaojing Wu
- Minhua Ye
- Guangyao Shi
- Shigang Lv
- Xingen Zhu
View Affiliations

Affiliations: Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Neurosurgery, Jiangxi Provincial Children's Hospital, Nanchang, Jiangxi 330006, P.R. China, Queen Mary School, Medical College, Nanchang University School of Medicine, Nanchang, Jiangxi 330031, P.R. China
Published online on: April 4, 2019 https://doi.org/10.3892/ijmm.2019.4157
Pages: 2387-2397
Copyright: © Hu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The most common and aggressive type of brain cancer in adults is glioblastoma multiforme (GBM), and hypoxia is a common feature of glioblastoma. As the histological features of glioma include capillary endothelial cell proliferation, they are highly prone to invading the surrounding normal brain tissue, which is often one of the reasons for the failure of treatment. However, the mechanisms involved in this process are not fully understood. MicroRNAs (miRs) are a class of non‑coding RNA that are able to inhibit the malignant progression of tumor cells through the regulation of downstream genes. In the present study, the low expression of miR‑576‑3p was detected in glioma samples and hypoxia‑treated glioma cells using a reverse transcription‑quantitative polymerase chain reaction. The present study focused on the effects of miR‑576‑3p on hypoxia‑induced glioma. The results of the functional experiments revealed that the overexpression of miR‑576‑3p significantly inhibited the migration and pro‑angiogenic abilities of the glioma cells under hypoxic conditions (P<0.05) compared with in the lentivirus‑miR‑negative control group. Furthermore, luciferase reporter gene assays were used to validate the hypothesis that miR‑576‑3p interacts with the 3'‑untranslated region of hypoxia‑inducible factor‑1α (HIF‑1α) and induces a reduction in the protein levels of matrix metalloproteinase‑2 and vascular endothelial growth factor. Rescue experiments demonstrated that the restoration of HIF‑1α expression attenuated the effect of miR‑576‑3p on the migration and proangiogenic abilities of glioma cells. In conclusion, the present study confirms that miR‑576‑3p is a novel GBM inhibitor and its inhibition of the migration and proangiogenic capacity of hypoxia‑induced glioma cells is mediated by HIF‑1α.

View Figures

View References

1	Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW and Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114:97–109. 2007. View Article : Google Scholar : PubMed/NCBI
2	Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 352:987–996. 2005. View Article : Google Scholar : PubMed/NCBI
3	Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY and Olson JJ: Exciting new advances in neuro-oncology: The avenue to a cure for malignant glioma. CA Cancer J Clin. 60:166–193. 2010. View Article : Google Scholar : PubMed/NCBI
4	Senger D, Cairncross JG and Forsyth PA: Long-term survivors of glioblastoma: Statistical aberration or important unrecognized molecular subtype. Cancer J. 9:214–221. 2003. View Article : Google Scholar : PubMed/NCBI
5	Brandes AA, Franceschi E, Gorlia T, Wick W, Jacobs AH, Baumert BG, van den Bent M, Weller M and Stupp R; European Organisation for Research and Treatment of Cancer Brain Tumour Group: Appropriate end-points for right results in the age of antiangiogenic agents: Future options for phase II trials in patients with recurrent glioblastoma. Eur J Cancer. 48:896–903. 2012. View Article : Google Scholar
6	Hou LC, Veeravagu A, Hsu AR and Tse VC: Recurrent glioblastoma multiforme: A review of natural history and management options. Neurosurg Focus. 20:E52006. View Article : Google Scholar : PubMed/NCBI
7	Soda Y, Myskiw C, Rommel A and Verma IM: Mechanisms of neovascularization and resistance to anti-angiogenic therapies in glioblastoma multiforme. J Mol Med (Berl). 91:439–448. 2013. View Article : Google Scholar
8	Zagzag D, Zhong H, Scalzitti JM, Laughner E, Simons JW and Semenza GL: Expression of hypoxia-inducible factor 1alpha in brain tumors: Association with angiogenesis, invasion, and progression. Cancer. 88:2606–2618. 2000. View Article : Google Scholar : PubMed/NCBI
9	Kakudo N, Morimoto N, Ogawa T, Taketani S and Kusumoto K: Hypoxia enhances proliferation of human adipose-derived stem cells via HIF-1a activation. PLoS One. 10:e01398902015. View Article : Google Scholar
10	Bae WY, Choi JS, Kim JE and Jeong JW: Cinnamic aldehyde suppresses hypoxia-induced angiogenesis via inhibition of hypoxia-inducible factor-1α expression during tumor progression. Biochem Pharmacol. 98:41–50. 2015. View Article : Google Scholar : PubMed/NCBI
11	Antica M, Kusic B, Hranilovic D, Dietz AB and Vuk-Pavlovic S: Cloning the cDNA for murine U2 snRNP-A' gene and its differential expression in lymphocyte development. Immunol Lett. 82:217–223. 2002. View Article : Google Scholar : PubMed/NCBI
12	Li HS, Zhou YN, Li L, Li SF, Long D, Chen XL, Zhang JB, Li YP and Feng L: WITHDRAWN: Mitochondrial targeting of HIF-1α inhibits hypoxia-induced apoptosis independently of its transcriptional activity. Free Radic Biol Med. 2018.
13	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
14	Esquela-Kerscher A and Slack FJ: Oncomirs-microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar : PubMed/NCBI
15	Griffiths-Jones S, Saini HK, van Dongen S and Enright AJ: miRBase: Tools for microRNA genomics. Nucleic Acids Res. 36:D154–D158. 2008. View Article : Google Scholar :
16	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
17	Shenouda SK and Alahari SK: MicroRNA function in cancer: Oncogene or a tumor suppressor. Cancer Metastasis Rev. 28:369–378. 2009. View Article : Google Scholar : PubMed/NCBI
18	Hossian AKMN, Sajib MS, Tullar PE, Mikelis CM and Mattheolabakis G: Multipronged activity of combinatorial miR-143 and miR-506 inhibits lung cancer cell cycle progression and angiogenesis in vitro. Sci Rep. 8:104952018. View Article : Google Scholar : PubMed/NCBI
19	Wang Y, Ouyang M, Wang Q and Jian Z: MicroRNA-142-3p inhibits hypoxia/reoxygenation-induced apoptosis and fibrosis of cardiomyocytes by targeting high mobility group box 1. Int J Mol Med. 38:1377–1386. 2016. View Article : Google Scholar : PubMed/NCBI
20	Li L, Sun P, Zhang C, Li Z and Zhou W: MiR-98 suppresses the effects of tumor-associated macrophages on promoting migration and invasion of hepatocellular carcinoma cells by regulating IL-10. Biochimie. 150:23–30. 2018. View Article : Google Scholar : PubMed/NCBI
21	Rainov NG and Heidecke V: Clinical development of experimental therapies for malignant glioma. Sultan Qaboos Univ Med J. 11:5–28. 2011.PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
23	Miletic H, Niclou SP, Johansson M and Bjerkvig R: Anti-VEGF therapies for malignant glioma: Treatment effects and escape mechanisms. Expert Opin Ther Targets. 13:455–468. 2009. View Article : Google Scholar : PubMed/NCBI
24	Cheng RF, Wang J, Zhang JY, Sun L, Zhao YR, Qiu ZQ, Sun BC and Sun Y: MicroRNA-506 is up-regulated in the development of pancreatic ductal adenocarcinoma and is associated with attenuated disease progression. Chin J Cancer. 35:642016. View Article : Google Scholar : PubMed/NCBI
25	Hong-Yuan W and Xiao-Ping C: miR-338-3p suppresses epithelial-mesenchymal transition and metastasis in human nonsmall cell lung cancer. Indian J Cancer. 52(Suppl 3): E168–E171. 2015. View Article : Google Scholar
26	Wu JH, Wang YH, Wang W, Shen W, Sang YZ, Liu L and Chen CM: MiR-18b suppresses high-glucose-induced proliferation in HRECs by targeting IGF-1/IGF1R signaling pathways. Int J Biochem Cell Biol. 73:41–52. 2016. View Article : Google Scholar : PubMed/NCBI
27	Zhou Y, Liu Y, Hu C and Jiang Y: MicroRNA-16 inhibits the proliferation, migration and invasion of glioma cells by targeting Sal-like protein 4. Int J Mol Med. 38:1768–1776. 2016. View Article : Google Scholar : PubMed/NCBI
28	Li Q, Zhou L, Wang M, Wang N, Li C, Wang J and Qi L: MicroRNA-613 impedes the proliferation and invasion of glioma cells by targeting cyclin-dependent kinase 14. Biomed Pharmacother. 98:636–642. 2018. View Article : Google Scholar : PubMed/NCBI
29	Liang Z, Li S, Xu X, Xu X, Wang X, Wu J, Zhu Y, Hu Z, Lin Y, Mao Y, et al: MicroRNA-576-3p inhibits proliferation in bladder cancer cells by targeting cyclin D1. Mol Cells. 38:130–137. 2015. View Article : Google Scholar : PubMed/NCBI
30	Xia Lv J, Xu K, Sun P, Ma E, Gao J, Zhou S, Zhang Q, Wang M, Chen FF, et al: miRNA expression patterns in chemoresistant breast cancer tissues. Biomed Pharmacother. 68:935–942. 2014. View Article : Google Scholar : PubMed/NCBI
31	Sun B, Zhang D, Zhang S, Zhang W, Guo H and Zhao X: Hypoxia influences vasculogenic mimicry channel formation and tumor invasion-related protein expression in melanoma. Cancer Lett. 249:188–197. 2007. View Article : Google Scholar
32	Liao D and Johnson RS: Hypoxia: A key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 26:281–290. 2007. View Article : Google Scholar : PubMed/NCBI
33	Wang GL, Jiang BH, Rue EA and Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 92:5510–5514. 1995. View Article : Google Scholar : PubMed/NCBI
34	Huang LE, Gu J, Schau M and Bunn HF: Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA. 95:7987–7992. 1998. View Article : Google Scholar : PubMed/NCBI
35	Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 3:721–732. 2003. View Article : Google Scholar : PubMed/NCBI
36	Papandreou I, Cairns RA, Fontana L, Lim AL and Denko NC: HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3:187–197. 2006. View Article : Google Scholar : PubMed/NCBI
37	Liu X, Chen S, Tu J, Cai W and Xu Q: HSP90 inhibits apoptosis and promotes growth by regulating HIF-1α abundance in hepatocellular carcinoma. Int J Mol Med. 37:825–835. 2016. View Article : Google Scholar : PubMed/NCBI
38	Shiau AL, Shen YT, Hsieh JL, Wu CL and Lee CH: Scutellaria barbata inhibits angiogenesis through downregulation of HIF-1 α in lung tumor. Environ Toxicol. 29:363–370. 2014. View Article : Google Scholar
39	Tang JH, Ma ZX, Huang GH, Xu QF, Xiang Y, Li N, Sidlauskas K, Zhang EE and Lv SQ: Downregulation of HIF-1a sensitizes U251 glioma cells to the temozolomide (TMZ) treatment. Exp Cell Res. 343:148–158. 2016. View Article : Google Scholar : PubMed/NCBI
40	Shi H, Zheng B, Wu Y, Tang Y, Wang L, Gao Y, Gong H, Du J and Yu R: Ubiquitin ligase Siah1 promotes the migration and invasion of human glioma cells by regulating HIF-1α signaling under hypoxia. Oncol Rep. 33:1185–1190. 2015. View Article : Google Scholar : PubMed/NCBI
41	Cui H, Wang Y, Huang H, Yu W, Bai M, Zhang L, Bryan BA, Wang Y, Luo J, Li D, et al: GPR126 protein regulates developmental and pathological angiogenesis through modulation of VEGFR2 receptor signaling. J Biol Chem. 289:34871–34885. 2014. View Article : Google Scholar : PubMed/NCBI
42	Gupta B, Chiang L, Chae K and Lee DH: Phenethyl isothiocyanate inhibits hypoxia-induced accumulation of HIF-1α and VEGF expression in human glioma cells. Food Chem. 141:1841–1846. 2013. View Article : Google Scholar : PubMed/NCBI
43	Takano S, Yoshii Y, Kondo S, Suzuki H, Maruno T, Shirai S and Nose T: Concentration of vascular endothelial growth factor in the serum and tumor tissue of brain tumor patients. Cancer Res. 56:2185–2190. 1999.
44	Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD and Semenza GL: Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 16:4604–4613. 1996. View Article : Google Scholar : PubMed/NCBI
45	Osenkowski P, Toth M and Fridman R: Processing, shedding, and endocytosis of membrane type 1-matrix metalloproteinase (MT1-MMP). J Cell Physiol. 200:2–10. 2004. View Article : Google Scholar : PubMed/NCBI
46	Schenk S, Hintermann E, Bilban M, Koshikawa N, Hojilla C, Khokha R and Quaranta V: Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution. J Cell Biol. 161:197–209. 2003. View Article : Google Scholar : PubMed/NCBI
47	Fujiwara S, Nakagawa K, Harada H, Nagato S, Furukawa K, Teraoka M, Seno T, Oka K, Iwata S and Ohnishi T: Silencing hypoxia-inducible factor-1alpha inhibits cell migration and invasion under hypoxic environment in malignant gliomas. Int J Oncol. 30:793–802. 2007.PubMed/NCBI