EphA3, induced by PC-1/PrLZ, contributes to the malignant progression of prostate cancer

Wu,Ruiqin; Wang,Hongtao; Wang,Jian; Wang,Peng; Huang,Fang; Xie,Bangxiang; Zhao,Yali; Li,Shanhu; Zhou,Jianguang

doi:10.3892/or.2014.3482

EphA3, induced by PC-1/PrLZ, contributes to the malignant progression of prostate cancer

Authors:
- Ruiqin Wu
- Hongtao Wang
- Jian Wang
- Peng Wang
- Fang Huang
- Bangxiang Xie
- Yali Zhao
- Shanhu Li
- Jianguang Zhou
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Affiliations: Laboratory of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing 100850, P.R. China
Published online on: September 16, 2014 https://doi.org/10.3892/or.2014.3482
Pages: 2657-2665

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Abstract

Our previous study revealed the potential linkage of PC-1/PrLZ, a novel isolated prostate-specific gene, to the progression of prostate cancer (PCa) in vitro and in vivo. To gain more insight into the mechanism of PC-1-induced promotion of PCa, expression analysis of differential genes induced by PC-1 was scanned by microarray. Among all the differentially expressed genes, EphA3 was altered to the greatest extent. EphA3 has been identified to be associated with multiple tumor progression. However, little is known concerning the function of EphA3 in PCa. In the present study, we aimed to ascertain whether EphA3 is induced by PC-1 and the functional significance of EphA3 expression in PCa. We found that overexpression of PC-1 increased the amount of EphA3 and that knockdown of PC-1 led to a decrease in EphA3 in PCa cells. The functional significance and mechanisms by which EphA3 contributes to PCa was investigated in vitro using cell lines, and in vivo using a mouse model and clinical specimens. The results showed that EphA3 enhanced the proliferation and survival of LNCaP cells and suppression of EphA3 inhibited the survival of C4-2B cells. EphA3 enhanced the tumor development of LNCaP cells in null mice. A positive correlation between the levels of EphA3 and the Gleason grade of PCa was identified in clinical PCa specimens. In addition, cellular localization changed with Gleason grade. We further detected that EphA3 increased phosphorylation of Akt (Ser473 and Thr308), indicating that EphA3 activated the Akt pathway. Taken together, EphA3 was induced by PC-1 and contributed to the malignant progression of prostate cancer. Our results provide the first demonstration that EphA3 is a novel promoter of human prostate cancer development and progression.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Baade PD, Youlden DR, Cramb SM, Dunn J and Gardiner RA: Epidemiology of prostate cancer in the Asia-Pacific region. Prostate Int. 1:47–58. 2013. View Article : Google Scholar : PubMed/NCBI
3	Wang R, Xu J, Saramaki O, et al: PrLZ, a novel prostate-specific and androgen-responsive gene of the TPD52 family, amplified in chromosome 8q21.1 and overexpressed in human prostate cancer. Cancer Res. 64:1589–1594. 2004. View Article : Google Scholar
4	Li L, Xie H, Liang L, et al: Increased PrLZ-mediated androgen receptor transactivation promotes prostate cancer growth at castration-resistant stage. Carcinogenesis. 34:257–267. 2013. View Article : Google Scholar
5	Zhang H, Wang J, Pang B, et al: PC-1/PrLZ contributes to malignant progression in prostate cancer. Cancer Res. 67:8906–8913. 2007. View Article : Google Scholar : PubMed/NCBI
6	Wang J, Zhang H, Liang RX, et al: Identification and characterization of the novel human prostate cancer-specific PC-1 gene promoter. Biochem Biophys Res Commun. 357:8–13. 2007. View Article : Google Scholar : PubMed/NCBI
7	Yu L, Shi QG, Qian XL, et al: PC-1 enhances c-myc gene expression in prostate cancer cells. Yi Chuan. 32:348–352. 2010.(In Chinese).
8	Wimmer-Kleikamp SH and Lackmann M: Eph-modulated cell morphology, adhesion and motility in carcinogenesis. IUBMB Life. 57:421–431. 2005. View Article : Google Scholar : PubMed/NCBI
9	Wood LD, Calhoun ES, Silliman N, et al: Somatic mutations of GUCY2F, EPHA3, and NTRK3 in human cancers. Hum Mutat. 27:1060–1061. 2006. View Article : Google Scholar : PubMed/NCBI
10	Brantley DM, Cheng N, Thompson EJ, et al: Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene. 21:7011–7026. 2002. View Article : Google Scholar : PubMed/NCBI
11	Vearing C, Lee FT, Wimmer-Kleikamp S, et al: Concurrent binding of anti-EphA3 antibody and ephrin-A5 amplifies EphA3 signaling and downstream responses: potential as EphA3-specific tumor-targeting reagents. Cancer Res. 65:6745–6754. 2005. View Article : Google Scholar : PubMed/NCBI
12	Keane N, Freeman C, Swords R and Giles FJ: EPHA3 as a novel therapeutic target in the hematological malignancies. Expert Rev Hematol. 5:325–340. 2012. View Article : Google Scholar : PubMed/NCBI
13	Guan M, Liu L, Zhao X, et al: Copy number variations of EphA3 are associated with multiple types of hematologic malignancies. Clin Lymphoma Myeloma Leuk. 11:50–53. 2011. View Article : Google Scholar : PubMed/NCBI
14	Day BW, Stringer BW, Al-Ejeh F, et al: EphA3 maintains tumorigenicity and is a therapeutic target in glioblastoma multiforme. Cancer Cell. 23:238–248. 2013. View Article : Google Scholar : PubMed/NCBI
15	Hafner C, Schmitz G, Meyer S, et al: Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers. Clin Chem. 50:490–499. 2004. View Article : Google Scholar : PubMed/NCBI
16	Singh AP, Bafna S, Chaudhary K, et al: Genome-wide expression profiling reveals transcriptomic variation and perturbed gene networks in androgen-dependent and androgen-independent prostate cancer cells. Cancer Lett. 259:28–38. 2008. View Article : Google Scholar
17	Zhang D, He D, Xue Y, et al: PrLZ protects prostate cancer cells from apoptosis induced by androgen deprivation via the activation of Stat3/Bcl-2 pathway. Cancer Res. 71:2193–2202. 2011. View Article : Google Scholar : PubMed/NCBI
18	van Bokhoven A, Varella-Garcia M, Korch C, et al: Molecular characterization of human prostate carcinoma cell lines. Prostate. 57:205–225. 2003.PubMed/NCBI
19	Wu X, Gong S, Roy-Burman P, Lee P and Culig Z: Current mouse and cell models in prostate cancer research. Endocr Relat Cancer. 20:R155–R170. 2013. View Article : Google Scholar : PubMed/NCBI
20	Wu RQ, Li QM, Shi QG, Zhang H, Qian XL, Yu L and Zhou JG: PC-1 can enhance transcription of EphA3, a member of RTK family, in prostate cancer cells. Chin J Biochem Mol Biol. 25:633–639. 2009.
21	Jeong SJ, Pise-Masison CA, Radonovich MF, Park HU and Brady JN: Activated AKT regulates NF-kappaB activation, p53 inhibition and cell survival in HTLV-1-transformed cells. Oncogene. 24:6719–6728. 2005. View Article : Google Scholar : PubMed/NCBI
22	Viglietto G, Motti ML, Bruni P, et al: Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27^Kip1 by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med. 8:1136–1144. 2002. View Article : Google Scholar : PubMed/NCBI
23	Vivanco I and Sawyers CL: The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2:489–501. 2002. View Article : Google Scholar : PubMed/NCBI
24	Wicks IP, Wilkinson D, Salvaris E and Boyd AW: Molecular cloning of HEK, the gene encoding a receptor tyrosine kinase expressed by human lymphoid tumor cell lines. Proc Natl Acad Sci USA. 89:1611–1615. 1992. View Article : Google Scholar : PubMed/NCBI
25	Wang R, Xu J, Mabjeesh N, et al: PrLZ is expressed in normal prostate development and in human prostate cancer progression. Clin Cancer Res. 13:6040–6048. 2007. View Article : Google Scholar : PubMed/NCBI
26	Li L, Zhang D, Zhang L, et al: PrLZ expression is associated with the progression of prostate cancer LNCaP cells. Mol Carcinog. 48:432–440. 2009. View Article : Google Scholar : PubMed/NCBI
27	Easty DJ and Bennett DC: Protein tyrosine kinases in malignant melanoma. Melanoma Res. 10:401–411. 2000. View Article : Google Scholar : PubMed/NCBI
28	Li QM, Wu RQ, Pan DR and Zhou JG: Construction and analysis of EphA3 gene stable-expressed NIH3T3 cell model. Lett Biotech. 20:609–611. 2009.