Upregulation of PREX2 promotes the proliferation and migration of hepatocellular carcinoma cells via PTEN‑AKT signaling

He,Shujie; Lin,Juan; Yu,Shaoping; Sun,Shijie

doi:10.3892/ol.2016.4164

Upregulation of PREX2 promotes the proliferation and migration of hepatocellular carcinoma cells via PTEN‑AKT signaling

Authors:
- Shujie He
- Juan Lin
- Shaoping Yu
- Shijie Sun
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Affiliations: Department of Hepatobiliary Surgery, Yantai Mountain Hospital, Yantai, Shandong 264000, P.R. China, Department of Hepatobiliary Surgery, Government Hospital of Yantai City, Yantai, Shandong 264000, P.R. China, Department of Hepatobiliary Surgery, Yuhuangding Hospital, Yantai, Shandong 264001, P.R. China
Published online on: January 29, 2016 https://doi.org/10.3892/ol.2016.4164
Pages: 2223-2228

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Abstract

Phosphatidylinositol‑3,4,5‑trisphosphate Rac exchanger 2 (PREX2), a regulator of the small guanosine triphosphatase Rac, demonstrates an inhibitory effect on the activity of phosphatase and tensin homolog (PTEN). Previously, PREX2 was implicated in the regulation of cell invasion in hepatocellular carcinoma (HCC). However, the exact role of PREX2 in the regulation of HCC cell proliferation and migration, as well as the underlying mechanisms, remains unclear. In the present study, reverse transcription‑quantitative polymerase chain reaction revealed that PREX2 was upregulated in HCC tissue compared with matched adjacent non‑tumorous tissue. In addition, the present study demonstrated that the messenger RNA and protein levels of PREX2 increased in human HCC HepG2, LH86, LMH and PLHC‑1 cell lines compared with normal human liver THLE‑3 cells. Overexpression of PREX2 significantly enhanced the proliferation and migration of HCC cells, and knockdown of PREX2 expression significantly suppressed the proliferation and migration of HCC cells. Additional investigation revealed that overexpression of PREX2 suppressed the activity of PTEN, leading to an enhancement in the activity of protein kinase B (AKT). By contrast, knockdown of PREX2 expression upregulated the activity of PTEN and suppressed the activity of AKT. Overall, the present study suggests that PREX2 promotes the proliferation and migration of HCC cells by inhibiting PTEN‑AKT signaling.

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1	Zhu AX: Molecularly targeted therapy for advanced hepatocellular carcinoma in: 2012 Current status and future perspectives. Semin Oncol. 39:493–502. 2012. View Article : Google Scholar : PubMed/NCBI
2	Psyrri A, Arkadopoulos N, Vassilakopoulou M, Smyrniotis V and Dimitriadis G: Pathways and targets in hepatocellular carcinoma. Expert Rev Anticancer Ther. 12:1347–1357. 2012. View Article : Google Scholar : PubMed/NCBI
3	Dimitrova V and Arcaro A: Targeting the PI3K/AKT/mTOR signaling pathway in medulloblastoma. Curr Mol Med. 15:82–93. 2015. View Article : Google Scholar : PubMed/NCBI
4	Ohta K, Hoshino H, Wang J, Ono S, Iida Y, Hata K, Huang SK, Colquhoun S and Hoon DS: MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A. Oncotarget. 6:3211–3224. 2015. View Article : Google Scholar : PubMed/NCBI
5	Wang Y, Hu C, Cheng J, Chen B, Ke Q, Lv Z, Wu J and Zhou Y: MicroRNA-145 suppresses hepatocellular carcinoma by targeting IRS1 and its downstream Akt signaling. Biochem Biophys Res Commun. 446:1255–1260. 2014. View Article : Google Scholar : PubMed/NCBI
6	Wang HY, Yang SL, Liang HF and Li CH: HBx protein promotes oval cell proliferation by up-regulation of cyclin D1 via activation of the MEK/ERK and PI3K/Akt pathways. Int J Mol Sci. 15:3507–3518. 2014. View Article : Google Scholar : PubMed/NCBI
7	Carnero A and Paramio JM: The PTEN/PI3K/AKT pathway in vivo, cancer mouse models. Front Oncol. 4:2522014. View Article : Google Scholar : PubMed/NCBI
8	Eng C: PTEN: One gene, many syndromes. Hum Mutat. 22:183–198. 2003. View Article : Google Scholar : PubMed/NCBI
9	Hers I, Vincent EE and Tavaré JM: Akt signalling in health and disease. Cell Signal. 23:1515–1527. 2011. View Article : Google Scholar : PubMed/NCBI
10	Donald S, Hill K, Lecureuil C, Barnouin R, Krugmann S, Coadwell John 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
11	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
12	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
13	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
14	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
15	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
16	Lan X, Xiao F, Ding Q, Liu J, Liu J, Li J, Zhang J and Tian DA: The effect of CXCL9 on the invasion ability of hepatocellular carcinoma through up-regulation of PREX2. J Mol Histol. 45:689–696. 2014. View Article : Google Scholar : PubMed/NCBI
17	Hung CH, Chiu YC, Chen CH and Hu TH: MicroRNAs in hepatocellular carcinoma: Carcinogenesis, progression, and therapeutic target. Biomed Res Int. 2014:4864072014. View Article : Google Scholar : PubMed/NCBI
18	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 : PubMed/NCBI
19	Salmena L, Carracedo A and Pandolfi PP: Tenets of PTEN tumor suppression. Cell. 133:403–414. 2008. View Article : Google Scholar : PubMed/NCBI
20	Trotman LC, Niki M, Dotan ZA, Koutcher JA, Di Cristofano A, Xiao A, Khoo AS, Roy-Burman P, Greenberg NM, Van Dyke T, et al: Pten dose dictates cancer progression in the prostate. PLoS Biol. 1:E592003. View Article : Google Scholar : PubMed/NCBI
21	Oishi N, Yamashita T and Kaneko S: Molecular biology of liver cancer stem cells. Liver Cancer. 3:71–84. 2014. View Article : Google Scholar : PubMed/NCBI
22	Pandiella A and Montero JC: Molecular pathways: P-Rex in cancer. Clin Cancer Res. 19:4564–4569. 2013. View Article : Google Scholar : PubMed/NCBI
23	Leslie NR: P-REX2a driving tumorigenesis by PTEN inhibition. Sci Signal. 2:pe682009. View Article : Google Scholar : PubMed/NCBI