CENPO expression regulates gastric cancer cell proliferation and is associated with poor patient prognosis

Cao,Yi; Xiong,Jianbo; Li,Zhengrong; Zhang,Guoyang; Tu,Yi; Wang,Lizhen; Jie,Zhigang

doi:10.3892/mmr.2019.10624

CENPO expression regulates gastric cancer cell proliferation and is associated with poor patient prognosis

Authors:
- Yi Cao
- Jianbo Xiong
- Zhengrong Li
- Guoyang Zhang
- Yi Tu
- Lizhen Wang
- Zhigang Jie
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Affiliations: Department of Gastrointestinal Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Pathology, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: August 29, 2019 https://doi.org/10.3892/mmr.2019.10624
Pages: 3661-3670
Copyright: © Cao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Gastric cancer (GC) is one of the most common malignancies worldwide; however, understanding of its development and carcinogenesis is currently limited. Centromere protein O (CENPO), is a newly discovered constitutive centromeric protein, associated with cell death. The expression of CENPO in human cancers, including GC, is currently unknown. The aim of the present study was to investigate the clinical association between CENPO and GC, and to elucidate the potential mechanisms of CENPO in the process of GC progression. The results demonstrated that CENPO was expressed at high levels in GC and was correlated with p‑TNM stage. In addition, CENPO was observed to be a marker of poor prognosis in patients with GC. Knockdown of CENPO contributed to GC cell growth inhibition and apoptosis induction. In addition, downregulation of CENPO expression suppressed GC cell growth in vivo. Furthermore, CENPO knockdown decreased ataxia telangiectasia mutated (ATM), cyclin D1 and c‑Jun expression, indicating that the ATM signaling pathway may be involved in CENPO‑mediated regulation of GC cell growth. In conclusion, increased CENPO expression may be associated with the aggressive tumor biology of GC and CENPO may present a novel therapeutic target and prognostic biomarker for patients with GC.

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1	Ferro A, Peleteiro B, Malvezzi M, Bosetti C, Bertuccio P, Levi F, Negri E, La Vecchia C and Lunet N: Worldwide trends in gastric cancer mortality (1980–2011), with predictions to 2015, and incidence by subtype. Eur J Cancer. 50:1330–1344. 2014. View Article : Google Scholar : PubMed/NCBI
2	Corso S and Giordano S: How can gastric cancer molecular profiling guide future therapies? Trends Mol Med. 22:534–544. 2016. View Article : Google Scholar : PubMed/NCBI
3	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
4	Bakhoum SF and Compton DA: Kinetochores and disease. Keeping microtubule dynamics in check! Curr Opin Cell Biol. 24:64–70. 2012. View Article : Google Scholar : PubMed/NCBI
5	Duensing A and Duensing S: Centrosomes, polyploidy and cancer. Adv Exp Med Biol. 676:93–103. 2010. View Article : Google Scholar : PubMed/NCBI
6	Kramer A, Neben K and Ho AD: Centrosome replication, genomic instability and cancer. Leukemia. 16:767–775. 2002. View Article : Google Scholar : PubMed/NCBI
7	Obuse C, Yang H, Nozaki N, Goto S, Okazaki T and Yoda K: Proteomics analysis of the centromere complex from HeLa interphase cells: UV-damaged DNA binding protein 1 (DDB-1) is a component of the CEN-complex, while BMI-1 is transiently co-localized with the centromeric region in interphase. Genes Cells. 9:105–120. 2004. View Article : Google Scholar : PubMed/NCBI
8	Izuta H, Ikeno M, Suzuki N, Tomonaga T, Nozaki N, Obuse C, Kisu Y, Goshima N, Nomura F, Nomura N and Yoda K: Comprehensive analysis of the ICEN (Interphase Centromere Complex) components enriched in the CENP-A chromatin of human cells. Genes to cells. 11:673–684. 2006. View Article : Google Scholar : PubMed/NCBI
9	Hori T, Okada M, Maenaka K and Fukagawa T: CENP-O class proteins form a stable complex and are required for proper kinetochore function. Mol Biol Cell. 19:843–854. 2008. View Article : Google Scholar : PubMed/NCBI
10	Denais CM, Gilbert RM, Isermann P, McGregor AL, te Lindert M, Weigelin B, Davidson PM, Friedl P, Wolf K and Lammerding J: Nuclear envelope rupture and repair during cancer cell migration. Science. 352:353–358. 2016. View Article : Google Scholar : PubMed/NCBI
11	Orthwein A, Noordermeer SM, Wilson MD, Landry S, Enchev RI, Sherker A, Munro M, Pinder J, Salsman J, Dellaire G, et al: A mechanism for the suppression of homologous recombination in G1 cells. Nature. 528:422–426. 2015. View Article : Google Scholar : PubMed/NCBI
12	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real time quantitative PCR and the 2(-Delta Delta C(T)). Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
13	Felciano RM, Bavari S, Richards DR, Billaud JN, Warren T, Panchal R and Kramer A: Predictive systems biology approach to broad-spectrum, host-directed drug target discovery in infectious diseases. Pac Symp Biocomput. 17–28. 2013.PubMed/NCBI
14	Krämer A, Green J, Pollard J Jr and Tugendreich S: Causal analysis approaches in ingenuity pathway analysis. Bioinformatics. 30:523–530. 2014. View Article : Google Scholar : PubMed/NCBI
15	McAinsh AD, Meraldi P, Draviam VM, Toso A and Sorger PK: The human kinetochore proteins Nnf1R and Mcm21R are required for accurate chromosome segregation. EMBO J. 25:4033–4049. 2006. View Article : Google Scholar : PubMed/NCBI
16	Gordon DJ, Resio B and Pellman D: Causes and consequences of aneuploidy in cancer. Nat Rev Genet. 13:189–203. 2012. View Article : Google Scholar : PubMed/NCBI
17	Liao WT, Song LB, Zhang HZ, Zhang X, Zhang L, Liu WL, Feng Y, Guo BH, Mai HQ, Cao SM, et al: Centromere protein H is a novel prognostic marker for nasopharyngeal carcinoma progression and overall patient survival. Clin Cancer Res. 13:508–514. 2007. View Article : Google Scholar : PubMed/NCBI
18	Mi YJ, Gao J, Xie JD, Cao JY, Cui SX, Gao HJ, Yao SP, Liu T, Zhang YY, Guo CH, et al: Prognostic relevance and therapeutic implications of centromere protein F expression in patients with esophageal squamous cell carcinoma. Dis Esophagus. 26:636–643. 2013. View Article : Google Scholar : PubMed/NCBI
19	Kagawa N, Hori T, Hoki Y, Hosoya O, Tsutsui K, Saga Y, Sado T and Fukagawa T: The CENP-O complex requirement varies among different cell types. Chromosome Res. 22:293–303. 2014. View Article : Google Scholar : PubMed/NCBI
20	Choi M, Kipps T and Kurzrock R: ATM Mutations in Cancer: Therapeutic Implications. Mol Cancer Ther. 15:1781–1791. 2016. View Article : Google Scholar : PubMed/NCBI
21	Karnitz LM and Zou L: Molecular pathways: Targeting ATR in cancer therapy. Clin Cancer Res. 21:4780–4785. 2015. View Article : Google Scholar : PubMed/NCBI
22	Stagni V, Manni I, Oropallo V, Mottolese M, Di Benedetto A, Piaggio G, Falcioni R, Giaccari D, Di Carlo S, Sperati F, et al: ATM kinase sustains HER2 tumorigenicity in breast cancer. Nat Commun. 6:68862015. View Article : Google Scholar : PubMed/NCBI
23	Liu R, Tang J, Ding C, Liang W, Zhang L, Chen T, Xiong Y, Dai X, Li W, Xu Y, et al: The depletion of ATM inhibits colon cancer proliferation and migration via B56γ2-mediated Chk1/p53/CD44 cascades. Cancer Lett. 390:48–57. 2017. View Article : Google Scholar : PubMed/NCBI
24	Chen WT, Ebelt ND, Stracker TH, Xhemalce B, Van Den Berg CL and Miller KM: ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion. Elife. 4:e072702015. View Article : Google Scholar :
25	Ortiz A, Garcia D and Vicente Y: Prognostic significance of cyclin D1 protein expression and gene amplification in invasive breast carcinoma. PLoS One. 12:e01880682017. View Article : Google Scholar : PubMed/NCBI
26	Qie S and Diehl JA: Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med. 94:1313–1326. 2016. View Article : Google Scholar : PubMed/NCBI
27	Vaites LP, Lian Z, Lee EK, Yin B, DeMicco A, Bassing CH and Diehl JA: ATM deficiency augments constitutively nuclear cyclin D1-driven genomic instability and lymphomagenesis. Oncogene. 33:129–133. 2014. View Article : Google Scholar : PubMed/NCBI
28	Hitomi M, Yang K, Stacey AW and Stacey DW: Phosphorylation of cyclin D1 regulated by ATM or ATR controls cell cycle progression. Mol Cell Biol. 28:5478–5493. 2008. View Article : Google Scholar : PubMed/NCBI
29	Li Y and Yang DQ: The ATM Inhibitor KU-55933 suppresses cell proliferation and induces apoptosis by blocking Akt in cancer cells with overactivated Akt. Mol Cancer Ther. 9:113–125. 2010. View Article : Google Scholar : PubMed/NCBI
30	Meng Q and Xia Y: c-Jun, at the crossroad of the signaling network. Protein Cell. 2:889–898. 2011. View Article : Google Scholar : PubMed/NCBI
31	Peluso I, Yarla NS, Ambra R, Pastore G and Perry G: MAPK signalling pathway in cancers: Olive products as cancer preventive and therapeutic agents, Semin. Cancer Biol. 56:185–195. 2019. View Article : Google Scholar
32	Lee SA, Dritschilo A and Jung M: Role of ATM in oxidative stress-mediated c-Jun phosphorylation in response to ionizing radiation and CdCl2. J Biol Chem. 276:11783–11790. 2001. View Article : Google Scholar : PubMed/NCBI