Tumor Biology

, Volume 37, Issue 9, pp 12855–12866 | Cite as

Overexpression of MYCN promotes proliferation of non-small cell lung cancer

  • Kun Liu
  • Shuo Wang
  • Yifei Liu
  • Jun Gu
  • Shudong Gu
  • Zhen Xu
  • Rui Zhang
  • Zhiwen Wang
  • Huaci Ma
  • Yingying Chen
  • Lili Ji
Original Article


V-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) is an oncogene that is known amplified and overexpressed in different human malignancies including small cell lung cancer. However, the role of MYCN in non-small cell lung cancer (NSCLC) development remains elusive. In the present study, Western blot and immunohistochemistry assays demonstrated that MYCN was overexpressed in NSCLC tumor tissues and cell lines. In addition, immunohistochemistry analysis revealed that upregulation of MYCN expression was positively correlated with a more invasive tumor phenotype and poor prognosis. In vitro studies using serum starvation-refeeding experiment and MYCN-siRNA transfection assay demonstrated that MYCN expression promoted proliferation of NSCLC cells, while MYCN knockdown led to decreased cell growth resulted from growth arrest of cell cycle at G0/G1 phase. Furthermore, upregulation and knockdown of sex-determining region Y-box 2 (SRY) (SOX2), which was a well-known oncogene, confirmed that MYCN might be a downstream gene of the transcription factor SOX2. Collectively, our finding suggested that MYCN might contribute to the progression of NSCLC by enhancing cell proliferation, and that targeting MYCN might provide beneficial effects for the clinical therapy of NSCLC.


MYCN SOX2 NSCLC Cell cycle Proliferation 



This work was supported by the National Natural Science Foundation of China (no. 81501975), University Science Research Project of Jiangsu Province (15KJB310013), Six Talent Peaks Project in Jiangsu Province (nos. 2014-YY-006 and WSN-059), Nantong Science and Technology Project (MS12015103 and HS2012025), and Nantong University Innovation Project (YKC15087).

Compliance with ethical standards

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.

Conflicts of interest



  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  3. 3.
    Ettinger DS, Akerley W, Bepler G, Blum MG, Chang A, et al. Non-small cell lung cancer. J Natl Compr Canc Netw. 2010;8(7):740–801.PubMedGoogle Scholar
  4. 4.
    Chen G, Yi XH. Pathology and genetics of disease and tumours of the lung, pleura in China. Zhonghua Bing Li Xue Za Zhi. 2005;34(8):490–3.PubMedGoogle Scholar
  5. 5.
    Ravdin PM, Davis G. Prognosis of patients with resected non-small cell lung cancer: impact of clinical and pathologic variables. Lung Cancer. 2006;52(2):207–12.CrossRefPubMedGoogle Scholar
  6. 6.
    Grandori C, Cowley SM, James LP, Eisenman RN. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu Rev Cell Dev Biol. 2000;16:653–99.CrossRefPubMedGoogle Scholar
  7. 7.
    Meyer N, Penn LZ. Reflecting on 25 years with MYC. Nat Rev Cancer. 2008;8(12):976–90.CrossRefPubMedGoogle Scholar
  8. 8.
    Nau MM, Brooks Jr BJ, Carney DN, Gazdar AF, Battey JF, et al. Human small-cell lung cancers show amplification and expression of the N-myc gene. Proc Natl Acad Sci U S A. 1986;83(4):1092–6.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Engelen E, Akinci U, Bryne JC, Hou J, Gontan C, et al. Sox2 cooperates with Chd7 to regulate genes that are mutated in human syndromes. Nat Genet. 2011;43(6):607–11.CrossRefPubMedGoogle Scholar
  10. 10.
    Liu K, Lin B, Zhao M, Yang X, Chen M, et al. The multiple roles for Sox2 in stem cell maintenance and tumorigenesis. Cell Signal. 2013;25(5):1264–71.CrossRefPubMedGoogle Scholar
  11. 11.
    Bass AJ, Watanabe H, Mermel CH, Yu S, Perner S, et al. SOX2 is an amplified lineage-survual oncogene in lung and esophageal squamous cell carcinomas. Nat Genet. 2009;41(11):1238–42.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hussenet T, Dali S, Exinger J, Monga B, Jost B, et al. SOX2 is an oncogene activated by recurrent 3q26.3 amplifications in human lung cell carcinomas. PLoS One. 2010;5(1):e8960.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Rudin CM1, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet. 2012;44(10):1111–6.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Wan C, Hou S, Ni R, Lv L, Ding Z, et al. MIF4G domain containing protein regulates cell cycle and hepatic carcinogenesis by antagonizing CDK2-dependent p27 stability. Oncogene. 2015;34(2):237–45.CrossRefPubMedGoogle Scholar
  15. 15.
    Wang Y, Liu F, Mao F, Hang Q, Huang X, et al. Interaction with cyclin H/cyclin-dependent kinase 7 (CCNH/CDK7) stabilizes C-terminal binding protein 2 (CtBP2) and promotes cancer cell migration. J Biol Chem. 2013;288(13):9028–34.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ji L, Li H, Gao P, Shang G, Zhang DD, Zhang N, et al. Nrf2 pathway regulates multidrug-resistance-associated protein 1 in small cell lung cancer. PLoS One. 2013;8(5):e63404.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wang Y, Wang Y, Xiang J, Ji F, Deng Y, et al. Knockdown of CRM1 inhibits the nuclear export of p27(Kip1) phosphorylated at serine 10 and plays a role in the pathogenesis of epithelial ovarian cancer. Cancer Lett. 2014;343(1):6–13.CrossRefPubMedGoogle Scholar
  18. 18.
    Wang Y, Yang S, Ni Q, He S, Zhao Y, et al. Overexpression of forkhead box J2 can decrease the migration of breast cancer cells. J Cell Biochem. 2012;113(8):2729–37.CrossRefPubMedGoogle Scholar
  19. 19.
    Wood SL, Pernemalm M, Crosbie PA, Whetton AD. The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat Rev. 2014;40(4):558–66.CrossRefPubMedGoogle Scholar
  20. 20.
    Bell E, Chen L, Liu T, Marshall GM, Lunec J, et al. MYCN oncoprotein targets and their therapeutic potential. Cancer Lett. 2010;293(2):144–57.CrossRefPubMedGoogle Scholar
  21. 21.
    Woo CW, Tan F, Cassano H, Lee J, Lee KC, et al. Use of RNA interference to elucidate the effect of MYCN on cell cycle in neuroblastoma. Pediatr Blood Cancer. 2008;50(2):208–12.CrossRefPubMedGoogle Scholar
  22. 22.
    Feng C, Wang T, Tang R, Wang J, Long H, et al. Silencing of the MYCN gene by siRNA delivered by folate receptor-targeted liposomes in LA-N-5 cells. Pediatr Surg Int. 2010;26(12):1185–91.CrossRefPubMedGoogle Scholar
  23. 23.
    Nara K, Kusafuka T, Yoneda A, Oue T, Sangkhathat S, et al. Silencing of MYCN by RNA interference induces growth inhibition, apoptotic activity and cell differentiation in a neuroblastoma cell line with MYCN amplification. Int J Oncol. 2007;30(5):1189–96.PubMedGoogle Scholar
  24. 24.
    Malynn BA, de Alboran IM, O’Hagan RC, Bronson R, Davidson L, et al. N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation. Genes Dev. 2000;14(11):1390–9.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Murphy DM, Buckley PG, Bryan K, Watters KM, Koster J, et al. Dissection of the oncogenic MYCN transcriptional network reveals a large set of clinically relevant cell cycle genes as drivers of neuroblastoma tumorigenesis. Mol Carcinog. 2011;50(6):403–11.CrossRefPubMedGoogle Scholar
  26. 26.
    Wegner M. SOX after SOX: SOXession regulates neurogenesis. Genes Dev. 2011;25:2423–8.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Kun Liu
    • 1
  • Shuo Wang
    • 1
    • 2
    • 3
  • Yifei Liu
    • 4
  • Jun Gu
    • 5
  • Shudong Gu
    • 6
  • Zhen Xu
    • 6
  • Rui Zhang
    • 5
  • Zhiwen Wang
    • 2
  • Huaci Ma
    • 7
  • Yingying Chen
    • 3
    • 6
  • Lili Ji
    • 2
    • 3
  1. 1.Department of Cardiothoracic SurgeryAffiliated Hospital of Nantong UniversityNantongChina
  2. 2.Department of PathologyMedical School of Nantong UniversityNantongChina
  3. 3.Jiangsu Province Key Laboratory for Inflammation and Molecular Target, Medical School of Nantong UniversityNantongChina
  4. 4.Department of PathologyAffiliated Hospital of Nantong UniversityNantongChina
  5. 5.Department of RespiratoryAffiliated Hospital of Nantong UniversityNantongChina
  6. 6.Department of OncologyAffiliated Hospital of Nantong UniversityNantongChina
  7. 7.Department of OtorhinolaryngologyAffiliated Hospital of Nantong UniversityNantongChina

Personalised recommendations