MicroRNA‑21 promotes migration and invasion of glioma cells via activation of Sox2 and β‑catenin signaling Retraction in /10.3892/mmr.2023.12982

Luo,Guoxuan; Luo,Wentao; Sun,Xiaohui; Lin,Jinzhi; Wang,Mo; Zhang,Yang; Luo,Weishi; Zhang,Yong

doi:10.3892/mmr.2016.5971

MicroRNA‑21 promotes migration and invasion of glioma cells via activation of Sox2 and β‑catenin signaling

Retraction in: /10.3892/mmr.2023.12982

Authors:
- Guoxuan Luo
- Wentao Luo
- Xiaohui Sun
- Jinzhi Lin
- Mo Wang
- Yang Zhang
- Weishi Luo
- Yong Zhang
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Affiliations: Department of Neurosurgery, Guangdong No. 2 Provincial People's Hospital, Guangzhou, Guangdong 510317, P.R. China
Published online on: November 28, 2016 https://doi.org/10.3892/mmr.2016.5971
Pages: 187-193
Copyright: © Luo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The expression of microRNA 21 (miR-21) has been reported to be upregulated in various types of cancer, including malignant gliomas. However, its functions and mechanisms in glioma remain to be fully elucidated. The present study established miRNA‑21 overexpression and knockdown cell lines using SRY‑box 2 (Sox2) small interfering RNA (siRNA) to knockdown expression and Sox2 cDNA was cloned into pcDNA 3.1 mammalian expression vector for ectopic expression. BIO and XAV‑939 were used for β‑catenin signaling activation and knockdown, respectively. Transwell chambers were used to assay the capacity of cells to migrate. The present study determined that increased expression of miR‑21 significantly promoted the migration and invasion of glioma cells, which was accompanied by an upregulated expression of the Sox2 protein. Sox2 overexpression also promoted glioma cell migration and invasion, whereas Sox2 siRNA markedly reduced the miR‑21‑enhanced migration and invasion of glioma cells, indicating Sox2 may act as a crucial mediator of miR‑21 function. Furthermore, miR‑21 also upregulated the protein expression level of β‑catenin, whereas anti‑miR‑21 and Sox2 knockdown significantly reduced β‑catenin expression. BIO, a β‑catenin specific agonist, enhanced migration and invasion of glioma cells. XAV‑939, an inhibitor of β‑catenin signaling, markedly inhibited the migration and invasion of glioma cells, suggesting that β‑catenin may be associated with miR‑21‑ and Sox2‑induced invasion of glioma cells. Notably, BIO restored the migration and invasion potential of glioma cells, which were inhibited by Sox2 siRNA and anti‑miR‑21. These findings indicated that β‑catenin may be an important downstream mediator of miR‑21 and Sox2. Therefore, the present study identified the miR‑21/Sox2/β‑catenin signaling pathway, which may regulate the migration and invasion of human glioma cells.

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1	Omuro A and DeAngelis LM: Glioblastoma and other malignant gliomas: A clinical review. JAMA. 310:1842–1850. 2013. View Article : Google Scholar : PubMed/NCBI
2	Zagzag D, Lukyanov Y, Lan L, Ali MA, Esencay M, Mendez O, Yee H, Voura EB and Newcomb EW: Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: Implications for angiogenesis and glioma cell invasion. Lab Invest. 86:1221–1232. 2006. View Article : Google Scholar : PubMed/NCBI
3	Brat DJ, Castellano-Sanchez AA, Hunter SB, Pecot M, Cohen C, Hammond EH, Devi SN, Kaur B and Van Meir EG: Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases and are formed by an actively migrating cell population. Cancer Res. 64:920–927. 2004. View Article : Google Scholar : PubMed/NCBI
4	Brat DJ and Van Meir EG: Vaso-occlusive and prothrombotic mechanisms associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma. Lab Invest. 84:397–405. 2004. View Article : Google Scholar : PubMed/NCBI
5	Harris AL: Hypoxia-a key regulatory factor in tumour growth. Nat Rev Cancer. 2:38–47. 2002. View Article : Google Scholar : PubMed/NCBI
6	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
7	Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, Iorio MV, Visone R, Sever NI, Fabbri M, et al: A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med. 353:1793–1801. 2005. View Article : Google Scholar : PubMed/NCBI
8	Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O, Barzilai A, Einat P, Einav U, Meiri E, et al: Identification of hundreds of conserved and nonconserved human microRNAs. Nature Genet. 37:766–770. 2005. View Article : Google Scholar : PubMed/NCBI
9	Krek A, Grün D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M and Rajewsky N: Combinatorial microRNA target predictions. Nat Genet. 37:495–500. 2005. View Article : Google Scholar : PubMed/NCBI
10	Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP and Burge CB: Prediction of mammalian microRNA targets. Cell. 115:787–798. 2003. View Article : Google Scholar : PubMed/NCBI
11	Kulshreshtha R, Ferracin M, Wojcik SE, Garzon R, Alder H, Agosto-Perez FJ, Davuluri R, Liu CG, Croce CM, Negrini M, et al: A microRNA signature of hypoxia. Mol Cell Biol. 27:1859–1867. 2007. View Article : Google Scholar : PubMed/NCBI
12	Ali N, Mah N, McLoughlin P and Costello CM: Identification of a hypoxia-responsive microRNA signature in lung endothelial cells. Irish J Med Sci. 181:S4142012.
13	Qu K, Lin T, Pang Q, Liu T, Wang Z, Tai M, Meng F, Zhang J, Wan Y, Mao P, et al: Extracellular miRNA-21 as a novel biomarker in glioma: Evidence from meta-analysis, clinical validation and experimental investigations. Oncotarget. 7:33994–34010. 2016.PubMed/NCBI
14	Shi R, Wang PY, Li XY, Chen JX, Li Y, Zhang XZ, Zhang CG, Jiang T, Li WB, Ding W and Cheng SJ: Exosomal levels of miRNA-21 from cerebrospinal fluids associated with poor prognosis and tumor recurrence of glioma patients. Oncotarget. 6:26971–26981. 2015. View Article : Google Scholar : PubMed/NCBI
15	Põlajeva J, Swartling FJ, Jiang Y, Singh U, Pietras K, Uhrbom L, Westermark B and Roswall P: miRNA-21 is developmentally regulated in mouse brain and is co-expressed with SOX2 in glioma. BMC Cancer. 12:3782012. View Article : Google Scholar : PubMed/NCBI
16	Gabriely G, Wurdinger T, Kesari S, Esau CC, Burchard J, Linsley PS and Krichevsky AM: MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol. 28:5369–5380. 2008. View Article : Google Scholar : PubMed/NCBI
17	Yang N, Hui L, Wang Y, Yang H and Jiang X: SOX2 promotes the migration and invasion of laryngeal cancer cells by induction of MMP-2 via the PI3K/Akt/mTOR pathway. Oncol Rep. 31:2651–2659. 2014.PubMed/NCBI
18	Yang N, Hui L, Wang Y, Yang H and Jiang X: Overexpression of SOX2 promotes migration, invasion, and epithelial-mesenchymal transition through the Wnt/β-catenin pathway in laryngeal cancer Hep-2 cells. Tumour Biol. 35:7965–7973. 2014. View Article : Google Scholar : PubMed/NCBI
19	Chen S, Xu Y, Chen Y, Li X, Mou W, Wang L, Liu Y, Reisfeld RA, Xiang R, Lv D and Li N: SOX2 gene regulates the transcriptional network of oncogenes and affects tumorigenesis of human lung cancer cells. PloS One. 7:e363262012. View Article : Google Scholar : PubMed/NCBI
20	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 : PubMed/NCBI
21	Steeg PS: Tumor metastasis: Mechanistic insights and clinical challenges. Nat Med. 12:895–904. 2006. View Article : Google Scholar : PubMed/NCBI
22	Bass AJ, Watanabe H, Mermel CH, Yu S, Perner S, Verhaak RG, Kim SY, Wardwell L, Tamayo P, Gat-Viks I, et al: SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet. 41:1238–1242. 2009. View Article : Google Scholar : PubMed/NCBI
23	Annovazzi L, Mellai M, Caldera V, Valente G and Schiffer D: SOX2 expression and amplification in gliomas and glioma cell lines. Cancer Genomics Proteomics. 8:139–147. 2011.PubMed/NCBI
24	Gangemi RM, Griffero F, Marubbi D, Perera M, Capra MC, Malatesta P, Ravetti GL, Zona GL and Daga A: SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity. Stem cells. 27:40–48. 2009. View Article : Google Scholar : PubMed/NCBI
25	Heddleston JM, Li Z, Lathia JD, Bao S, Hjelmeland AB and Rich JN: Hypoxia inducible factors in cancer stem cells. Br J Cancer. 102:789–795. 2010. View Article : Google Scholar : PubMed/NCBI
26	Hall CL, Bafico A, Dai J, Aaronson SA and Keller ET: Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res. 65:7554–7560. 2005.PubMed/NCBI
27	Osawa T and Shibuya M: Targeting cancer cells resistant to hypoxia and nutrient starvation to improve anti-angiogeneic therapy. Cell Cycle. 12:2519–2520. 2013. View Article : Google Scholar : PubMed/NCBI
28	Wilson WR and Hay MP: Targeting hypoxia in cancer therapy. Nat Rev Cancer. 11:393–410. 2011. View Article : Google Scholar : PubMed/NCBI
29	Melillo G: Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev. 26:341–352. 2007. View Article : Google Scholar : PubMed/NCBI
30	Ambros V: microRNAs: Tiny regulators with great potential. Cell. 107:823–826. 2001. View Article : Google Scholar : PubMed/NCBI
31	Wang D, Qiu C, Zhang H, Wang J, Cui Q and Yin Y: Human microRNA oncogenes and tumor suppressors show significantly different biological patterns: From functions to targets. PloS One. 5(pii): e130672010.PubMed/NCBI
32	Si ML, Zhu S, Wu H, Lu Z, Wu F and Mo YY: miR-21-mediated tumor growth. Oncogene. 26:2799–2803. 2007. View Article : Google Scholar : PubMed/NCBI
33	Ben-Porath I, Thomson MW, Carey VJ, Ge R, Bell GW, Regev A and Weinberg RA: An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 40:499–507. 2008. View Article : Google Scholar : PubMed/NCBI
34	Berezovsky AD, Poisson LM, Cherba D, Webb CP, Transou AD, Lemke NW, Hong X, Hasselbach LA, Irtenkauf SM, Mikkelsen T and deCarvalho AC: Sox2 promotes malignancy in glioblastoma by regulating plasticity and astrocytic differentiation. Neoplasia. 16:193–206. 206.e119-e125, 2014.
35	Yang N, Hui L, Wang Y, Yang H and Jiang X: Overexpression of SOX2 promotes migration, invasion, and epithelial-mesenchymal transition through the Wnt/β-catenin pathway in laryngeal cancer Hep-2 cells. Tumour Biol. 35:7965–7673. 2014. View Article : Google Scholar : PubMed/NCBI