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ZWINT is the next potential target for lung cancer therapy

  • Fang Peng
  • Qiang Li
  • Shao-Qing Niu
  • Guo-Ping Shen
  • Ying Luo
  • Ming ChenEmail author
  • Yong BaoEmail author
Original Article – Cancer Research
  • 16 Downloads

Abstract

Purpose

We aimed to analyze the expression of ZWINT, NUSAP1, DLGAP5, and PRC1 in tumor tissues and adjacent tissues with public data.

Methods

The expression patterns of four genes were detected in cancer tissues and adjacent tissues by qRT-PCR. The overall survival analysis was used to explore these genes in lung adenocarcinoma and squamous cell carcinoma patients. Knockdown assays were used to select the most suitable gene among these four genes. Cell function assays with the knockdown gene were conducted in A549 and NCL H226 cells. The role of the knockdown gene in lung cancer was dissected in a mice tumor model. Transcriptome sequencing analyses with the knockdown gene were analyzed.

Results

Overexpression of these genes was significantly detected in cancer tissues (P < 0.01). Overall survival revealed that high expression of these genes is closely related with poor prognosis of lung adenocarcinoma patients (P < 0.05). Knockdown of ZWINT reduced proliferation in NCI H226 and A549 cells (P < 0.05). Knockdown also inhibited cell migration, invasion, apoptosis, and colony formation (P < 0.05). ZWINT knockdown reduced tumor volume (P < 0.05). Transcriptome sequencing of ZWINT knockdown-treated A549 and NCI H226 cells indicated that 100 and 426 differentially expressed genes were obtained, respectively. Gene ontology analysis suggested that binding, biological regulation, and multicellular organismal processes were the most enriched. KEGG analysis revealed that TNF, P53, and PI3K signal networks would be the most potential ZWINT-related pathways and were identified by Western blot analysis.

Conclusions

ZWINT may be a novel target for lung cancer therapy.

Keywords

Lung cancer ZWINT Differentially expressed genes Gene ontology KEGG 

Notes

Author contributions

FP, QL, and S-QN: bioinformatics analysis and writing of the manuscript. G-PS and YL: the discussion. MC and YB: discussion and comments on an earlier version of the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported in part by the National Natural Science Foundation of China (no. 81602661), the Natural Science Foundation of Guangdong Province, China (no. 2016A030310164). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

The author(s) declare that they have no competing interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards The Research Ethics Committee of Sun Yat-Sen University approved the collection of tissue samples for research.

Informed consent

None.

Supplementary material

432_2018_2823_MOESM1_ESM.tif (204 kb)
Supplementary material 1 Figure S1. mRNA abundance of ZWINT, NUSAP1, DLGAP5, and PRC1 in small cell lung cancer (SCLC), lung adenocarcinoma, and the paired adjacent normal tissues. (a) Gene expression in SCLC and the paired adjacent normal tissues. (b) Gene expression in lung adenocarcinoma and the paired adjacent normal tissues (TIF 204 KB)

References

  1. Bartkova J et al (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434:864–870.  https://doi.org/10.1038/nature03482 CrossRefPubMedGoogle Scholar
  2. Bass AJ et al (2009) SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet 41:1238–1242.  https://doi.org/10.1038/ng.465 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Brendle A et al (2009) Single nucleotide polymorphisms in chromosomal instability genes and risk and clinical outcome of breast cancer: a Swedish prospective case–control study. Eur J Cancer 45:435–442.  https://doi.org/10.1016/j.ejca.2008.10.001 CrossRefPubMedGoogle Scholar
  4. Chen L et al (2015a) High levels of nucleolar spindle-associated protein and reduced levels of BRCA1 expression predict poor prognosis in triple-negative breast cancer. PLoS One 10:e0140572.  https://doi.org/10.1371/journal.pone.0140572 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Chen L, Zhuo D, Chen J, Yuan H (2015b) Screening feature genes of lung carcinoma with DNA microarray analysis. Int J Clin Exp Med 8:12161–12171PubMedPubMedCentralGoogle Scholar
  6. Chou HY, Wang TH, Lee SC, Hsu PH, Tsai MD, Chang CL, Jeng YM (2011) Phosphorylation of NuSAP by Cdk1 regulates its interaction with microtubules in mitosis. Cell Cycle 10:4083–4089.  https://doi.org/10.4161/cc.10.23.18200 CrossRefPubMedGoogle Scholar
  7. Cooper WA, Lam DC, O’Toole SA, Minna JD (2013) Molecular biology of lung cancer. J Thorac Dis 5(Suppl 5):S479–S490  https://doi.org/10.3978/j.issn.2072-1439.2013.08.03 CrossRefPubMedPubMedCentralGoogle Scholar
  8. de Bruin EC et al (2014) Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346:251–256.  https://doi.org/10.1126/science.1253462 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Ding L et al (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455:1069–1075.  https://doi.org/10.1038/nature07423 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Dolly SO, Collins DC, Sundar R, Popat S, Yap TA (2017) Advances in the development of molecularly targeted agents in non-small-cell lung cancer. Drugs 77:813–827.  https://doi.org/10.1007/s40265-017-0732-2 CrossRefPubMedGoogle Scholar
  11. Engeland K (2018) Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death Differ 25:114–132.  https://doi.org/10.1038/cdd.2017.172 CrossRefPubMedGoogle Scholar
  12. Espinosa AM et al (2013) Mitosis is a source of potential markers for screening and survival and therapeutic targets in cervical cancer. PLoS One 8:e55975.  https://doi.org/10.1371/journal.pone.0055975 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gomez CR et al (2013) Prognostic value of discs large homolog 7 transcript levels in prostate cancer. PLoS One 8:e82833.  https://doi.org/10.1371/journal.pone.0082833 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Gordon CA, Gong X, Ganesh D, Brooks JD (2017) NUSAP1 promotes invasion and metastasis of prostate cancer. Oncotarget 8:29935–29950.  https://doi.org/10.18632/oncotarget.15604 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Gorgoulis VG et al (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434:907–913.  https://doi.org/10.1038/nature03485 CrossRefPubMedGoogle Scholar
  16. Hanibuchi M, Kim SJ, Fidler IJ, Nishioka Y (2014) The molecular biology of lung cancer brain metastasis: an overview of current comprehensions and future perspectives. J Med Investig 61:241–253CrossRefGoogle Scholar
  17. Hassan M, Watari H, AbuAlmaaty A, Ohba Y, Sakuragi N (2014) Apoptosis and molecular targeting therapy in cancer. Biomed Res Int 2014:150845.  https://doi.org/10.1155/2014/150845 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hata A et al (2013) Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: comparison between T790M mutation-positive and mutation-negative populations. Cancer 119:4325–4332.  https://doi.org/10.1002/cncr.28364 CrossRefPubMedGoogle Scholar
  19. Hu CK, Ozlu N, Coughlin M, Steen JJ, Mitchison TJ (2012) Plk1 negatively regulates PRC1 to prevent premature midzone formation before cytokinesis. Mol Biol Cell 23:2702–2711.  https://doi.org/10.1091/mbc.E12-01-0058 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Huang X, Zhang X, Farahvash B, Olumi AF (2007) Novel targeted pro-apoptotic agents for the treatment of prostate cancer. J Urol 178:1846–1854.  https://doi.org/10.1016/j.juro.2007.06.039 CrossRefPubMedGoogle Scholar
  21. Imielinski M et al (2012) Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150:1107–1120.  https://doi.org/10.1016/j.cell.2012.08.029 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kanehira M et al (2007) Oncogenic role of MPHOSPH1, a cancer-testis antigen specific to human bladder cancer. Cancer Res 67:3276–3285.  https://doi.org/10.1158/0008-5472.can-06-3748 CrossRefPubMedGoogle Scholar
  23. Kikuchi T et al (2003) Expression profiles of non-small cell lung cancers on cDNA microarrays: identification of genes for prediction of lymph-node metastasis and sensitivity to anti-cancer drugs. Oncogene 22:2192–2205.  https://doi.org/10.1038/sj.onc.1206288 CrossRefPubMedGoogle Scholar
  24. Kops GJ, Weaver BA, Cleveland DW (2005) On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer 5:773–785.  https://doi.org/10.1038/nrc1714 CrossRefPubMedGoogle Scholar
  25. Kwak EL et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693–1703.  https://doi.org/10.1056/NEJMoa1006448 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Lin YM, Furukawa Y, Tsunoda T, Yue CT, Yang KC, Nakamura Y (2002) Molecular diagnosis of colorectal tumors by expression profiles of 50 genes expressed differentially in adenomas and carcinomas. Oncogene 21:4120–4128.  https://doi.org/10.1038/sj.onc.1205518 CrossRefPubMedGoogle Scholar
  27. Lin KH et al (2018) RNA-seq transcriptome analysis of breast cancer cell lines under shikonin treatment. Sci Rep 8:2672.  https://doi.org/10.1038/s41598-018-21065-x CrossRefPubMedPubMedCentralGoogle Scholar
  28. Luo HW et al (2016) Protein regulator of cytokinesis 1 overexpression predicts biochemical recurrence in men with prostate cancer. Biomed Pharmacother 78:116–120.  https://doi.org/10.1016/j.biopha.2016.01.004 CrossRefPubMedGoogle Scholar
  29. Maemondo M et al (2010) Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR N. Engl J Med 362:2380–2388.  https://doi.org/10.1056/NEJMoa0909530 CrossRefGoogle Scholar
  30. McGuire S (2016) World Cancer Report 2014. Geneva, Switzerland: World Health Organization, International Agency for Research on Cancer, WHO Press, 2015. Adv Nutr 7:418–419.  https://doi.org/10.3945/an.116.012211 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Nakamura T et al (2004) Genome-wide cDNA microarray analysis of gene expression profiles in pancreatic cancers using populations of tumor cells and normal ductal epithelial cells selected for purity by laser microdissection. Oncogene 23:2385–2400.  https://doi.org/10.1038/sj.onc.1207392 CrossRefPubMedGoogle Scholar
  32. Obama K, Ura K, Satoh S, Nakamura Y, Furukawa Y (2005) Up-regulation of PSF2, a member of the GINS multiprotein complex in intrahepatic cholangiocarcinoma. Oncol Rep 14:701–706PubMedGoogle Scholar
  33. Pao W et al (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 101:13306–13311.  https://doi.org/10.1073/pnas.0405220101 CrossRefPubMedGoogle Scholar
  34. Ramalingam SS, Owonikoko TK, Khuri FR (2011) Lung cancer: new biological insights and recent therapeutic advances. CA Cancer J Clin 61:91–112.  https://doi.org/10.3322/caac.20102 CrossRefPubMedGoogle Scholar
  35. Remon J, Moran T, Majem M, Reguart N, Dalmau E, Marquez-Medina D, Lianes P (2014) Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: a new era begins. Cancer Treat Rev 40:93–101.  https://doi.org/10.1016/j.ctrv.2013.06.002 CrossRefPubMedGoogle Scholar
  36. Rooney M, Devarakonda S, Govindan R (2013) Genomics of squamous cell lung cancer Oncologist 18:707–716.  https://doi.org/10.1634/theoncologist.2013-0063 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Satow R et al (2010) Combined functional genome survey of therapeutic targets for hepatocellular carcinoma. Clin Cancer Res 16:2518–2528.  https://doi.org/10.1158/1078-0432.ccr-09-2214 CrossRefPubMedGoogle Scholar
  38. Scagliotti GV et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543–3551.  https://doi.org/10.1200/jco.2007.15.0375 CrossRefPubMedGoogle Scholar
  39. Schneider MA et al (2017) AURKA, DLGAP5, TPX2, KIF11 and CKAP5: Five specific mitosis-associated genes correlate with poor prognosis for non-small cell lung cancer patients. Int J Oncol 50:365–372.  https://doi.org/10.3892/ijo.2017.3834 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Sharma SV, Bell DW, Settleman J, Haber DA (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7:169–181.  https://doi.org/10.1038/nrc2088 CrossRefPubMedGoogle Scholar
  41. Shi YX, Yin JY, Shen Y, Zhang W, Zhou HH, Liu ZQ (2017) Genome-scale analysis identifies NEK2, DLGAP5 and ECT2 as promising diagnostic and prognostic biomarkers in human lung cancer. Sci Rep 7:8072.  https://doi.org/10.1038/s41598-017-08615-5 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Shimo A, Nishidate T, Ohta T, Fukuda M, Nakamura Y, Katagiri T (2007) Elevated expression of protein regulator of cytokinesis 1, involved in the growth of breast cancer cells. Cancer Sci 98:174–181.  https://doi.org/10.1111/j.1349-7006.2006.00381.x CrossRefPubMedGoogle Scholar
  43. Siegel R et al (2012) Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin 62:220–241.  https://doi.org/10.3322/caac.21149 CrossRefPubMedGoogle Scholar
  44. Spigel DR et al (2011) Randomized, double-blind, placebo-controlled, phase II trial of sorafenib and erlotinib or erlotinib alone in previously treated advanced non-small-cell lung cancer. J Clin Oncol 29:2582–2589.  https://doi.org/10.1200/jco.2010.30.7678 CrossRefPubMedGoogle Scholar
  45. Sundar R, Soong R, Cho BC, Brahmer JR, Soo RA (2014) Immunotherapy in the treatment of non-small cell lung cancer. Lung Cancer 85:101–109.  https://doi.org/10.1016/j.lungcan.2014.05.005 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Wang H et al (2004) Human Zwint-1 specifies localization of Zeste White 10 to kinetochores and is essential for mitotic checkpoint signaling. J Biol Chem 279:54590–54598.  https://doi.org/10.1074/jbc.M407588200 CrossRefPubMedGoogle Scholar
  47. Woo Seo D, Yeop You S, Chung WJ, Cho DH, Kim JS, Su Oh J (2015) Zwint-1 is required for spindle assembly checkpoint function and kinetochore-microtubule attachment during oocyte meiosis. Sci Rep 5:15431.  https://doi.org/10.1038/srep15431 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Wu X et al (2017) Nucleolar and spindle associated protein 1 promotes the aggressiveness of astrocytoma by activating the Hedgehog signaling pathway. J Exp Clin Cancer Res 36:127.  https://doi.org/10.1186/s13046-017-0597-y CrossRefPubMedPubMedCentralGoogle Scholar
  49. Xie C et al (2011) KOBAS 2.0: a web server for annotation and identification of enriched pathways and diseases. Nucleic Acids Res 39:W316–W322.  https://doi.org/10.1093/nar/gkr483 CrossRefPubMedPubMedCentralGoogle Scholar
  50. Xu Z, Zhou Y, Cao Y, Dinh TL, Wan J, Zhao M (2016) Identification of candidate biomarkers and analysis of prognostic values in ovarian cancer by integrated bioinformatics analysis. Med Oncol 33:130.  https://doi.org/10.1007/s12032-016-0840-y CrossRefPubMedGoogle Scholar
  51. Zarogoulidis K et al (2013) Immunomodifiers in combination with conventional chemotherapy in small cell lung cancer: a phase II randomized study. Drug Des Dev Ther 7:611–617.  https://doi.org/10.2147/dddt.s43184 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Radiation OncologyThe First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouPeople’s Republic of China
  2. 2.Department of Organ Transplantation and General Surgery, Second Xiangya HospitalCentral South UniversityChangshaPeople’s Republic of China
  3. 3.Department of Clinical Laboratory, Guangdong General HospitalGuangdong Academy of Medical SciencesGuangzhouPeople’s Republic of China
  4. 4.Department of Radiation Oncology, Zhejiang Key Laboratory of Radiation OncologyZhejiang Cancer HospitalHangzhouPeople’s Republic of China

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