Programmed cell death 4 and BCR‑ABL fusion gene expression are negatively correlated in chronic myeloid leukemia

Zhang,Xia; Liu,Riming; Huang,Baohua; Zhang,Xiaolu; Yu,Weijuan; Bao,Cuixia; Li,Jie; Sun,Chengming

doi:10.3892/ol.2016.4942

Programmed cell death 4 and BCR‑ABL fusion gene expression are negatively correlated in chronic myeloid leukemia

Authors:
- Xia Zhang
- Riming Liu
- Baohua Huang
- Xiaolu Zhang
- Weijuan Yu
- Cuixia Bao
- Jie Li
- Chengming Sun
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Affiliations: Department of Laboratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China
Published online on: August 3, 2016 https://doi.org/10.3892/ol.2016.4942
Pages: 2976-2981

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Abstract

Programmed cell death 4 (PDCD4) is a tumor suppressor that inhibits carcinogenesis, tumor progression and invasion by preventing gene transcription and translation. Downregulation of PDCD4 expression has been identified in multiple types of human cancer, however, to date, the function of PDCD4 in leukemia has not been investigated. In the present study, PDCD4 mRNA and protein expression was investigated in 50 patients exhibiting various phases of chronic myeloid leukemia (CML) and 20 healthy individuals by reverse transcription‑quantitative polymerase chain reaction and western blot analysis. PDCD4 expression and cell proliferation was also investigated following treatment with the tyrosine kinase inhibitor, imatinib, in K562 cells. The results demonstrated that PDCD4 mRNA and protein expression was decreased in all CML samples when compared with healthy controls, who expressed high levels of PDCD4 mRNA and protein. No significant differences in PDCD4 expression were identified between chronic phase, accelerated phase and blast phase CML patients. In addition, PDCD4 expression was negatively correlated with BCR‑ABL gene expression (r=‑0.6716; P<0.001). Furthermore, K562 cells treated with imatinib exhibited significantly enhanced PDCD4 expression. These results indicate that downregulation of PDCD4 expression may exhibit a critical function in the progression and malignant proliferation of human CML.

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1	Quintás-Cardama A and Cortes JE: Chronic myeloid leukemia: Diagnosis and treatment. Mayo Clin Proc. 81:973–988. 2006. View Article : Google Scholar : PubMed/NCBI
2	Quintás-Cardama A and Cortes JE: Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood. 113:1619–1630. 2009. View Article : Google Scholar : PubMed/NCBI
3	Perrotti D, Jamieson C, Goldman J and Skorski T: Chronic myeloid leukemia: Mechanisms of blastic transformation. J Clin Invest. 120:2254–2264. 2010. View Article : Google Scholar : PubMed/NCBI
4	Yang HS, Cho MH, Zakowicz H, Hegamyer G, Sonenberg N and Colburn NH: A novel function of the MA-3 domains in transformation and translation suppressor Pdcd4 is essential for its binding to eukaryotic translation initiation factor 4A. Mol Cell Biol. 24:3894–3906. 2004. View Article : Google Scholar : PubMed/NCBI
5	Singh P, Wedeken L, Waters LC, Carr MD and Klempnauer KH: Pdcd4 directly binds the coding region of c-myb mRNA and suppresses its translation. Oncogene. 30:4864–4873. 2011. View Article : Google Scholar : PubMed/NCBI
6	Biyanee A, Ohnheiser J, Singh P and Klempnauer KH: A novel mechanism for the control of translation of specific mRNAs by tumor suppressor protein Pdcd4: Inhibition of translation elongation. Oncogene. 34:1384–1392. 2015. View Article : Google Scholar : PubMed/NCBI
7	Hilliard A, Hilliard B, Zheng SJ, Sun H, Miwa T, Song W, Göke R and Chen YH: Translational regulation of autoimmune inflammation and lymphoma genesis by programmed cell death 4. J Immunol. 177:8095–8102. 2006. View Article : Google Scholar : PubMed/NCBI
8	Jansen AP, Camalier CE and Colburn NH: Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis. Cancer Res. 65:6034–6041. 2005. View Article : Google Scholar : PubMed/NCBI
9	Chen Y, Knösel T, Kristiansen G, Pietas A, Garber ME, Matsuhashi S, Ozaki I and Petersen I: Loss of PDCD4 expression in human lung cancer correlates with tumour progression and prognosis. J Pathol. 200:640–646. 2003. View Article : Google Scholar : PubMed/NCBI
10	Zhang H, Ozaki I, Mizuta T, Hamajima H, Yasutake T, Eguchi Y, Ideguchi H, Yamamoto K and Matsuhashi S: Involvement of programmed cell death 4 in transforming growth factor-beta1-induced apoptosis in human hepatocellular carcinoma. Oncogene. 25:6101–6112. 2006. View Article : Google Scholar : PubMed/NCBI
11	Mudduluru G, Medved F, Grobholz R, Jost C, Gruber A, Leupold JH, Post S, Jansen A, Colburn NH and Allgayer H: Loss of programmed cell death 4 expression marks adenoma-carcinoma transition, correlates inversely with phosphorylated protein kinase B, and is an independent prognostic factor in resected colorectal cancer. Cancer. 110:1697–1707. 2007. View Article : Google Scholar : PubMed/NCBI
12	Wei ZT, Zhang X, Wang XY, Gao F, Zhou CJ, Zhu FL, Wang Q, Gao Q, Ma CH, Sun WS, et al: PDCD4 inhibits the malignant phenotype of ovarian cancer cells. Cancer Sci. 100:1408–1413. 2009. View Article : Google Scholar : PubMed/NCBI
13	Gao F, Zhang P, Zhou C, Li J, Wang Q, Zhu F, Ma C, Sun W and Zhang L: Frequent loss of PDCD4 expression in human glioma: Possible role in the tumorigenesis of glioma. Oncol Rep. 17:123–128. 2007.PubMed/NCBI
14	Yang HS, Knies JL, Stark C and Colburn NH: Pdcd4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation. Oncogene. 22:3712–3720. 2003. View Article : Google Scholar : PubMed/NCBI
15	Yang HS, Matthews CP, Clair T, Wang Q, Baker AR, Li CC, Tan TH and Colburn NH: Tumorigenesis suppressor Pdcd4 down-regulates mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion. Mol Cell Biol. 26:1297–1306. 2006. View Article : Google Scholar : PubMed/NCBI
16	Leupold JH, Yang HS, Colburn NH, Asangani I, Post S and Allgayer H: Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors. Oncogene. 26:4550–4562. 2007. View Article : Google Scholar : PubMed/NCBI
17	Wang Q, Sun Z and Yang HS: Downregulation of tumor suppressor Pdcd4 promotes invasion and activates both beta-catenin/Tcf and AP-1-dependent transcription in colon carcinoma cells. Oncogene. 27:1527–1535. 2008. View Article : Google Scholar : PubMed/NCBI
18	Wang Q, Sun ZX, Allgayer H and Yang HS: Downregulation of E-cadherin is an essential event in activating beta-catenin/Tcf-dependent transcription and expression of its target genes in Pdcd4 knockdown cells. Oncogene. 29:128–138. 2010. View Article : Google Scholar : PubMed/NCBI
19	Vardiman JW, Harris NL and Brunning RD: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 100:2292–2302. 2002. 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	Neviani P, Santhanam R, Trotta R, Notari M, Blaser BW, Liu S, Mao H, Chang JS, Galietta A, Uttam A, et al: The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein. Cancer Cell. 8:355–368. 2005. View Article : Google Scholar : PubMed/NCBI
22	Beck Z, Kiss A, Tóth FD, Szabó J, Bácsi A, Balogh E, Borbély A, Telek B, Kovács E, Oláh E and Rak K: Alterations of P53 and RB genes and the evolution of the accelerated phase of chronic myeloid leukemia. Leuk Lymphoma. 38:587–597. 2000. View Article : Google Scholar : PubMed/NCBI
23	Peng C, Chen Y, Yang Z, Zhang H, Osterby L, Rosmarin AG and Li S: PTEN is a tumor suppressor in CML stem cells and BCR-ABL-induced leukemias in mice. Blood. 115:626–635. 2010. View Article : Google Scholar : PubMed/NCBI
24	Riccioni R, Lulli V, Castelli G, Biffoni M, Tiberio R, Pelosi E, LoCoco F and Testa U: miR-21 is overexpressed in NPM1-mutant acute myeloid leukemias. Leuk Res. 39:221–228. 2015. View Article : Google Scholar : PubMed/NCBI
25	Song X, Zhang X, Wang X, Zhu F, Guo C, Wang Q, Shi Y, Wang J, Chen Y and Zhang L: Tumor suppressor gene PDCD4 negatively regulates autophagy by inhibiting the expression of autophagy-related gene ATG5. Autophagy. 9:743–755. 2013. View Article : Google Scholar : PubMed/NCBI
26	Ozpolat B, Akar U, Steiner M, ZorrillaCalancha I, TiradoGomez M, Colburn N, Danilenko M, Kornblau S and Berestein GL: Programmed cell death-4 tumor suppressor protein contributes to retinoic acid-induced terminal granulocytic differentiation of human myeloid leukemia cells. Mol Cancer Res. 5:95–108. 2007. View Article : Google Scholar : PubMed/NCBI
27	Cash AC and Andrews J: Fine scale analysis of gene expression in Drosophila melanogaster gonads reveals Programmed cell death 4 promotes the differentiation of female germline stem cells. BMC Dev Biol. 12:42012. View Article : Google Scholar : PubMed/NCBI
28	Zhou M, Zeng J, Wang X, Wang X, Huang T, Fu Y, Sun T, Jia J and Chen C: Histone demethylase RBP2 decreases miR-21 in blast crisis of chronic myeloid leukemia. Oncotarget. 6:1249–1261. 2015. View Article : Google Scholar : PubMed/NCBI
29	Cilloni D and Saglio G: Molecular pathways: BCR-ABL. Clin Cancer Res. 18:930–937. 2012. View Article : Google Scholar : PubMed/NCBI
30	Parmar S, Smith J, Sassano A, Uddin S, Katsoulidis E, Majchrzak B, Kambhampati S, Eklund EA, Tallman MS, Fish EN and Platanias LC: Differential regulation of the p70 S6 kinase pathway by interferon alpha (IFNalpha) and imatinib mesylate (STI571) in chronic myelogenous leukemia cells. Blood. 106:2436–2443. 2005. View Article : Google Scholar : PubMed/NCBI
31	Carayol N, Katsoulidis E, Sassano A, Altman JK, Druker BJ and Platanias LC: Suppression of programmed cell death 4 (PDCD4) protein expression by BCR-ABL-regulated engagement of themTOR/p70 S6 kinase pathway. J Biol Chem. 283:8601–8610. 2008. View Article : Google Scholar : PubMed/NCBI
32	Woodard J, Sassano A, Hay N and Platanias LC: Statin-dependent suppression of the Akt/mammalian target of rapamycin signaling cascade and programmed cell death 4 up-regulation in renal cell carcinoma. Clin Cancer Res. 14:4640–4649. 2008. View Article : Google Scholar : PubMed/NCBI