Knockdown of PREX2a inhibits the malignant phenotype of osteosarcoma cells Retraction in /10.3892/mmr.2022.12630

Dai,Zixun; Xie,Jie; Lei,Pengfei; Hu,Yihe

doi:10.3892/mmr.2015.4728

Knockdown of PREX2a inhibits the malignant phenotype of osteosarcoma cells

Retraction in: /10.3892/mmr.2022.12630

Authors:
- Zixun Dai
- Jie Xie
- Pengfei Lei
- Yihe Hu
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Affiliations: Department of Orthopedics, Xiangya Hospital of Central South University, Changsha, Hunan 410008, P.R. China
Published online on: December 28, 2015 https://doi.org/10.3892/mmr.2015.4728
Pages: 1930-1936

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Abstract

Phosphatidylinositol‑3,4,5‑trisphosphate‑dependent Rac exchange factor 2a (PREX2a), which is a regulator of the small guanosine triphosphatase Rac, has recently been reported to have an oncogenic role via the suppression of phosphatase and tensin homolog deleted on chromosome ten (PTEN) activity, and the subsequent activation of phosphoinositide 3‑kinase (PI3K) signaling. However, the detailed role of PREX2a in osteosarcoma (OS) remains unclear. Reverse transcription quantitative polymerase chain reaction and western blotting was used to detect mRNA and protein levels. MTT assay was performed to examine cell proliferation and a Transwell assay and wound healing assay were conducted to examine cell invasion and migration. The present study demonstrated that PREX2a was markedly upregulated in OS cell lines, as compared with in normal osteoblast hFOB1.19 cells. In addition, knockdown of PREX2a expression significantly inhibited OS cell proliferation, whereas overexpression of PREX2a markedly promoted OS cell proliferation. Inhibition of PREX2a also markedly suppressed the invasion and migration of OS cells, at least partly by suppressing the protein expression of matrix metalloproteinase (MMP)2 and MMP9. Conversely, upregulation of PREX2a enhanced OS cell invasion and migration. In addition, PI3K signaling activity was significantly reduced following knockdown of PREX2a, and this was accompanied by an upregulation of PTEN activity. The results of the present study suggested that PREX2a may act as an oncogene in OS via the inhibition of PTEN activity and activation of PI3K signaling.

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1	Thompson LD: Osteosarcoma. Ear Nose Throat J. 92:288–290. 2013.PubMed/NCBI
2	PosthumaDeBoer J, Witlox MA, Kaspers GJ and van Royen BJ: Molecular alterations as target for therapy in metastatic osteosarcoma: A review of literature. Clin Exp Metastasis. 28:493–503. 2011. View Article : Google Scholar : PubMed/NCBI
3	Yang J and Zhang W: New molecular insights into osteosarcoma targeted therapy. Curr Opin Oncol. 25:398–406. 2013. View Article : Google Scholar : PubMed/NCBI
4	Namløs HM, Meza-Zepeda LA, Barøy T, Østensen IH, Kresse SH, Kuijjer ML, Serra M, Bürger H, Cleton-Jansen AM and Myklebost O: Modulation of the osteosarcoma expression phenotype by microRNAs. PLoS One. 7:e480862012. View Article : Google Scholar : PubMed/NCBI
5	Braccini L, Ciraolo E, Martini M, Pirali T, Germena G, Rolfo K and Hirsch E: PI3K keeps the balance between metabolism and cancer. Adv Biol Regul. 52:389–405. 2012. View Article : Google Scholar : PubMed/NCBI
6	Wu P and Hu YZ: PI3K/Akt/mTOR pathway inhibitors in cancer: A perspective on clinical progress. Curr Med Chem. 17:4326–4341. 2010. View Article : Google Scholar : PubMed/NCBI
7	Burris HA III: Overcoming acquired resistance to anticancer therapy: Focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol. 71:829–842. 2013. View Article : Google Scholar : PubMed/NCBI
8	Perry JA, Kiezun A, Tonzi P, Van Allen EM, Carter SL, Baca SC, Cowley GS, Bhatt AS, Rheinbay E, Pedamallu CS, et al: Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci USA. 111:E5564–E5573. 2014. View Article : Google Scholar : PubMed/NCBI
9	Yang L, Shu T, Liang Y, Gu W, Wang C, Song X, Fan C and Wang W: GDC-0152 attenuates the malignant progression of osteosarcoma promoted by ANGPTL2 via PI3K/AKT but not p38MAPK signaling pathway. Int J Oncol. 46:1651–1658. 2015.PubMed/NCBI
10	Eng C: PTEN: One gene, many syndromes. Hum Mutat. 22:183–198. 2003. View Article : Google Scholar : PubMed/NCBI
11	Hodakoski C, Hopkins BD, Barrows D, Mense SM, Keniry M, Anderson KE, Kern PA, Hawkins PT, Stephens LR and Parsons R: Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis. Proc Natl Acad Sci USA. 111:155–160. 2014. View Article : Google Scholar :
12	Donald S, Hill K, Lecureuil C, Barnouin R, Krugmann S, John Coadwell W, Andrews SR, Walker SA, Hawkins PT, Stephens LR and Welch HC: P-Rex2, a new guanine-nucleotide exchange factor for Rac. FEBS Lett. 572:172–176. 2004. View Article : Google Scholar : PubMed/NCBI
13	Fine B, Hodakoski C, Koujak S, Su T, Saal LH, Maurer M, Hopkins B, Keniry M, Sulis ML, Mense S, et al: Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a. Science. 325:1261–1265. 2009. View Article : Google Scholar : PubMed/NCBI
14	Guo B, Liu L, Yao J, Ma R, Chang D, Li Z, Song T and Huang C: miR-338-3p suppresses gastric cancer progression through a PTEN-AKT axis by targeting P-REX2a. Mol Cancer Res. 12:313–321. 2014. View Article : Google Scholar : PubMed/NCBI
15	Chen X, Pan M, Han L, Lu H, Hao X and Dong Q: miR-338-3p suppresses neuroblastoma proliferation, invasion and migration through targeting PREX2a. FEBS Lett. 587:3729–3737. 2013. View Article : Google Scholar : PubMed/NCBI
16	Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, Ivanova E, Watson IR, Nickerson E, Ghosh P, et al: Melanoma genome sequencing reveals frequent PREX2 mutations. Nature. 485:502–506. 2012.PubMed/NCBI
17	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
18	Rosenfeldt H, Vázquez-Prado J and Gutkind JS: P-REX2, a novel PI-3-kinase sensitive Rac exchange factor. FEBS Lett. 572:167–171. 2004. View Article : Google Scholar : PubMed/NCBI
19	Leslie NR: P-REX2a driving tumorigenesis by PTEN inhibition. Sci Signal. 2:pe682009. View Article : Google Scholar : PubMed/NCBI
20	Qin J, Xie Y, Wang B, Hoshino M, Wolff DW, Zhao J, Scofield MA, Dowd FJ, Lin MF and Tu Y: Upregulation of PIP3-dependent Rac exchanger 1 (P-Rex1) promotes prostate cancer metastasis. Oncogene. 28:1853–1863. 2009. View Article : Google Scholar : PubMed/NCBI
21	Montero JC, Seoane S, Ocaña A and Pandiella A: P-Rex1 participates in Neuregulin-ErbB signal transduction and its expression correlates with patient outcome in breast cancer. Oncogene. 30:1059–1071. 2011. View Article : Google Scholar
22	Donald S, Humby T, Fyfe I, Segonds-Pichon A, Walker SA, Andrews SR, Coadwell WJ, Emson P, Wilkinson LS and Welch HC: P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination. Proc Natl Acad Sci USA. 105:4483–4488. 2008. View Article : Google Scholar : PubMed/NCBI
23	Pandiella A and Montero JC: Molecular pathways: P-Rex in cancer. Clin Cancer Res. 19:4564–4569. 2013. View Article : Google Scholar : PubMed/NCBI
24	Wang JY, Wu PK, Chen PC, Yen CC, Hung GY, Chen CF, Hung SC, Tsai SF, Liu CL, Chen TH and Chen WM: Manipulation therapy prior to diagnosis induced primary osteosarcoma metastasis - from clinical to basic research. PLoS One. 9:e965712014. View Article : Google Scholar
25	Fromigué O, Hamidouche Z and Marie PJ: Blockade of the RhoA-JNK-c-Jun-MMP2 cascade by atorvastatin reduces osteosarcoma cell invasion. J Biol Chem. 283:30549–30556. 2008. View Article : Google Scholar : PubMed/NCBI
26	Chueh FS, Chen YY, Huang AC, Ho HC, Liao CL, Yang JS, Kuo CL and Chung JG: Bufalin-inhibited migration and invasion in human osteosarcoma U-2 OS cells is carried out by suppression of the matrix metalloproteinase-2, ERK, and JNK signaling pathways. Environ Toxicol. 29:21–29. 2014. View Article : Google Scholar
27	Jin J, Cai L, Liu ZM and Zhou XS: miRNA-218 inhibits osteosarcoma cell migration and invasion by down-regulating of TIAM1, MMP2 and MMP9. Asian Pac J Cancer Prev. 14:3681–3684. 2013. View Article : Google Scholar : PubMed/NCBI