Downregulation of DLL4 predicts poor survival in non‑small cell lung cancer patients due to promotion of lymph node metastasis

Liu,Hongzhou; Peng,Jie; Zhao,Meizhen; Ma,Pei; Zhong,Jun; Li,Shuang; Lu,Zhongxin

doi:10.3892/or.2018.6679

Downregulation of DLL4 predicts poor survival in non‑small cell lung cancer patients due to promotion of lymph node metastasis

Authors:
- Hongzhou Liu
- Jie Peng
- Meizhen Zhao
- Pei Ma
- Jun Zhong
- Shuang Li
- Zhongxin Lu
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Affiliations: Department of Medical Laboratory, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China, Department of Stomatology, Wuhan Medical and Healthcare Center for Women and Children, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430015, P.R. China, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Second Oncology Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China, Department of Urologic Surgery, Wuhan Medical and Healthcare Center for Women and Children, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430015, P.R. China
Published online on: August 31, 2018 https://doi.org/10.3892/or.2018.6679
Pages: 2988-2996

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Abstract

Delta-like 4 (DLL4) is a membrane‑bound ligand, which belongs to the Notch signaling pathway and plays important roles in angiogenesis and vascular development. The expression of DLL4 in non‑small cell lung cancer (NSCLC) remains unclear. Therefore, DLL4 expression was detected in clinical specimens using quantum dots (QDs)‑immunohistochemistry (IHC) and lung cancer cell lines by quantitative real‑time polymerase chain reaction. The protein levels of DLL4 were decreased in the tumor tissues of NSCLC patients and lung cancer cell lines. Kaplan‑Meier analysis indicated that low expression of DLL4 predicted poor survival rate of NSCLC patients. A549 and A427 cells transfected with pCMV‑DLL4 exhibited reduced cell proliferation, migration and invasion using MTT assay, wound healing assay and Transwell assay. These data indicate that DLL4 represents a new prognostic biomarker for NSCLC, and DLL4 overexpression inhibits cell proliferation and metastasis in vitro.

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1	Peng J, Liu HZ, Zhong J, Deng ZF, Tie CR, Rao Q, Xu W, You T, Li J, Cai CB, et al: MicroRNA-187 is an independent prognostic factor in lung cancer and promotes lung cancer cell invasion via targeting of PTRF. Oncol Rep. 36:2609–2618. 2016. View Article : Google Scholar : PubMed/NCBI
2	Gkolfinopoulos S and Mountzios G: Beyond EGFR and ALK: targeting rare mutations in advanced non-small cell lung cancer. Ann Transl Med. 6:1422018. View Article : Google Scholar : PubMed/NCBI
3	Gallant JN and Lovly CM: Established, emerging and elusive molecular targets in the treatment of lung cancer. J Pathol. 244:565–577. 2018. View Article : Google Scholar : PubMed/NCBI
4	Chen C, Zhao Z, Liu Y and Mu D: MicroRNA-99a is downregulated and promotes proliferation, migration and invasion in non-small cell lung cancer A549 and H1299 cells. Oncol Lett. 9:1128–1134. 2015. View Article : Google Scholar : PubMed/NCBI
5	Liu HZ, Du CX, Luo J, Qiu XP, Li ZH, Lou QY, Yin Z and Zheng F: A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations. Oncotarget. 8:2708–2718. 2017.PubMed/NCBI
6	Mishra N, Timilsina U, Ghimire D, Dubey RC and Gaur R: Downregulation of cytochrome c oxidase subunit 7A1 expression is important in enhancing cell proliferation in adenocarcinoma cells. Biochem Biophys Res Commun. 482:713–719. 2017. View Article : Google Scholar : PubMed/NCBI
7	Gridley T: Notch signaling in the vasculature. Curr Top Dev Biol. 92:277–309. 2010. View Article : Google Scholar : PubMed/NCBI
8	Phng LK and Gerhardt H: Angiogenesis: A team effort coordinated by notch. Dev Cell. 16:196–208. 2009. View Article : Google Scholar : PubMed/NCBI
9	Gale NW, Dominguez MG, Noguera I, Pan L, Hughes V, Valenzuela DM, Murphy AJ, Adams NC, Lin HC, Holash J, et al: Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci USA. 101:15949–15954. 2004. View Article : Google Scholar : PubMed/NCBI
10	Siekmann AF and Lawson ND: Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature. 445:781–784. 2007. View Article : Google Scholar : PubMed/NCBI
11	Patel NS, Li JL, Generali D, Poulsom R, Cranston DW and Harris AL: Up-regulation of Delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res. 65:8690–8697. 2005. View Article : Google Scholar : PubMed/NCBI
12	Patel NS, Dobbie MS, Rochester M, Steers G, Poulsom R, Le Monnier K, Cranston DW, Li JL and Harris AL: Upregulation of endothelial Delta-like 4 expressioncorrelates with vessel maturation in bladder cancer. Clin Cancer Res. 12:4836–4844. 2006. View Article : Google Scholar : PubMed/NCBI
13	Jubb AM, Soilleux EJ, Turley H, Steers G, Parker A, Low I, Blades J, Li JL, Allen P, Leek R, et al: Expression of vascular Notch ligand Delta-like 4 and inflammatory markers in breast cancer. Am J Pathol. 176:2019–2028. 2010. View Article : Google Scholar : PubMed/NCBI
14	Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, Lin HC, Yancopoulos GD and Thurston G: Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature. 444:1032–1037. 2006. View Article : Google Scholar : PubMed/NCBI
15	Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y, Kowalski J, Watts RJ, Callahan C, Kasman I, et al: Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature. 444:1083–1087. 2006. View Article : Google Scholar : PubMed/NCBI
16	Li JL, Sainson RCA, Shi W, Leek R, Harrington LS, Preusser M, Biswas S, Turley H, Heikamp E, Hainfellner JA and Harris AL: Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res. 67:11244–11253. 2007. View Article : Google Scholar : PubMed/NCBI
17	International Union against Cancer: TNM Classification of Malignant Tumours. Sobin LH, Gospodarowicz MK and Wittekind C: 7th edition. Wiley-Blackwell; Hoboken, NJ: 2009
18	Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger K, Yatabe Y, Powell CA, Beer D, Riely G, Garg K, et al: International association for the study of lung cancer/american thoracic society/european respiratory society: International multidisciplinary classification of lung adenocarcinoma: Executive summary. Proc Am Thorac Soc. 8:381–385. 2011. View Article : Google Scholar : PubMed/NCBI
19	Kononen J, Bubendorf L, Kallioniemi A, Bärlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G and Kallioniemi OP: Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 4:844–847. 1998. View Article : Google Scholar : PubMed/NCBI
20	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
21	Zhong Z, Xia Y, Wang P, Liu B and Chen Y: Low expression of microRNA-30c promotes invasion by inducing epithelial mesenchymal transition in non-small cell lung cancer. Mol Med Rep. 10:2575–2579. 2014. View Article : Google Scholar : PubMed/NCBI
22	Yu G, Herazo-Maya JD, Nukui T, Romkes M, Parwani A, Juan-Guardela BM, Robertson J, Gauldie J, Siegfried JM, Kaminski N, et al: Matrix metalloproteinase-19 promotes metastatic behavior in vitro and is associated with increased mortality in non-small cell lung cancer. Am J Respir Crit Care Med. 190:780–790. 2014. View Article : Google Scholar : PubMed/NCBI
23	Zhong K, Chen K, Han L and Li B: MicroRNA-30b/c inhibits non-small cell lung cancer cell proliferation by targeting Rab18. BMC Cancer. 14:7032014. View Article : Google Scholar : PubMed/NCBI
24	Biyashev D, Veliceasa D, Topczewski J, Topczewska JM, Mizgirev I, Vinokour E, Reddi AL, Licht JD, Revskoy SY and Volpert OV: miR-27b controls venous specification and tip cell fate. Blood. 119:2679–2687. 2012. View Article : Google Scholar : PubMed/NCBI
25	Bridge G, Monteiro R, Henderson S, Emuss V, Lagos D, Georgopoulou D, Patient R and Boshoff C: The microRNA-30 family targets DLL4 to modulate endothelial cell behavior during angiogenesis. Blood. 120:5063–5072. 2012. View Article : Google Scholar : PubMed/NCBI
26	Scehnet JS, Jiang W, Kumar SR, Krasnoperov V, Trindade A, Benedito R, Djokovic D, Borges C, Ley EJ, Duarte A, et al: Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood. 109:4753–4760. 2007. View Article : Google Scholar : PubMed/NCBI
27	Haller BK, Bråve A, Wallgard E, Roswall P, Sunkari VG, Mattson U, Hallengärd D, Catrina SB, Hellström M and Pietras K: Therapeutic efficacy of a DNA vaccine targeting the endothelial tip cell antigen delta-like ligand 4 in mammary carcinoma. Oncogene. 29:4276–4286. 2010. View Article : Google Scholar : PubMed/NCBI
28	Kalén M, Heikura T, Karvinen H, Nitzsche A, Weber H, Esser N, Ylä-Herttuala S and Hellström M: Gamma-secretase inhibitor treatment promotes VEGF-A-driven blood vessel growth and vascular leakage but disrupts neovascular perfusion. PLoS One. 6:e187092011. View Article : Google Scholar : PubMed/NCBI
29	Segarra M, Williams CK, de la Luz SM, Bernardo M, McCormick PJ, Maric D, Regino C, Choyke P and Tosato G: Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth. Blood. 112:1904–1911. 2008. View Article : Google Scholar : PubMed/NCBI
30	Hellström M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, et al: Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature. 445:776–780. 2007. View Article : Google Scholar : PubMed/NCBI
31	Leslie JD, Ariza-McNaughton L, Bermange AL, McAdow R, Johnson SL and Lewis J: Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis. Development. 134:839–844. 2007. View Article : Google Scholar : PubMed/NCBI
32	Trindade A, Djokovic D, Gigante J, Mendonça L and Duarte A: Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo. BMC Cancer. 17:1892017. View Article : Google Scholar : PubMed/NCBI