Overexpression of the Notch3 receptor and its ligand Jagged1 in human clinically non-functioning pituitary adenomas

Lu,Runchun; Gao,Hua; Wang,Hongyun; Cao,Lei; Bai,Jiwei; Zhang,Yazhuo

doi:10.3892/ol.2013.1113

Overexpression of the Notch3 receptor and its ligand Jagged1 in human clinically non-functioning pituitary adenomas

Authors:
- Runchun Lu
- Hua Gao
- Hongyun Wang
- Lei Cao
- Jiwei Bai
- Yazhuo Zhang
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Affiliations: Beijing Neurosurgical Institute, Capital Medical University, Dongcheng, Beijing 100050, P.R. China, Neurosurgical Department, Beijing Tiantan Hospital, Capital Medical University, Dongcheng, Beijing 100050, P.R. China
Published online on: January 7, 2013 https://doi.org/10.3892/ol.2013.1113
Pages: 845-851

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Abstract

Human clinically non-functioning pituitary adenomas (NFPAs) primarily cause headaches, visual impairment and hypopituitarism due to the effect of the mass of the tumor. Surgery is the first-line treatment for these tumors. To date, no efficacious medical therapy exists for non-functioning adenomas. Previous studies have demonstrated that the Notch3 receptor is involved in the pathogenesis of various types of malignancies, including human NFPAs. The current study focused on the expression of the Notch3 receptor and its ligand Jagged1 in three types of pituitary adenomas and in the normal pituitary gland. Using quantitative real-time RT‑PCR assays and western blot analyses, upregulated Notch3 and Jagged1 were observed in human NFPAs, but not in normal human pituitary glands or in hormone-secreting adenomas. Furthermore, Notch3 was positively correlated with Jagged1 at the mRNA and protein levels. These data indicate that Notch3 and Jagged1 may play an important role in the initiation and proliferation of human non-functioning adenomas, and there may be an interaction between Notch3 and Jagged1 in this process. Our study further elucidates the role of the Notch3 signaling pathway in the tumorigenesis of human NFPAs and provides a potential therapeutic target for the medical treatment of these tumors.

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1	Buurman H and Saeger W: Subclinical adenomas in postmortem pituitaries: classification and correlations to clinical data. Eur J Endocrinol. 154:753–758. 2006. View Article : Google Scholar : PubMed/NCBI
2	Saeger W, Lüdecke DK, Buchfelder M, Fahlbusch R, Quabbe HJ and Petersenn S: Pathohistological classification of pituitary tumors: 10 years of experience with the German Pituitary Tumor Registry. Eur J Endocrinol. 156:203–216. 2007.PubMed/NCBI
3	Greenman Y and Stern N: Non-functioning pituitary adenomas. Best Pract Res Clin Endocrinol Metab. 23:625–638. 2009. View Article : Google Scholar
4	Jaffe CA: Clinically non-functioning pituitary adenoma. Pituitary. 9:317–321. 2006. View Article : Google Scholar : PubMed/NCBI
5	Black PM, Hsu DW, Klibanski A, et al: Hormone production in clinically nonfunctioning pituitary adenomas. J Neurosurg. 66:244–250. 1987. View Article : Google Scholar : PubMed/NCBI
6	Gittoes NJ: Current perspectives on the pathogenesis of clinically non-functioning pituitary tumours. J Endocrinol. 157:177–186. 1998. View Article : Google Scholar : PubMed/NCBI
7	Katznelson L, Alexander JM and Klibanski A: Clinical review 45: Clinically nonfunctioning pituitary adenomas. J Clin Endocrinol Metab. 76:1089–1094. 1993.PubMed/NCBI
8	Korbonits M and Carlsen E: Recent clinical and pathophysiological advances in non-functioning pituitary adenomas. Horm Res. 71(Suppl 2): 123–130. 2009. View Article : Google Scholar
9	Colao A, Pivonello R, Di Somma C, Savastano S, Grasso LF and Lombardi G: Medical therapy of pituitary adenomas: effects on tumor shrinkage. Rev Endocr Metab Disord. 10:111–123. 2009. View Article : Google Scholar : PubMed/NCBI
10	Colao A, Di Somma C, Pivonello R, Faggiano A, Lombardi G and Savastano S: Medical therapy for clinically non-functioning pituitary adenomas. Endocr Relat Cancer. 15:905–915. 2008. View Article : Google Scholar : PubMed/NCBI
11	Bianchi S, Dotti MT and Federico A: Physiology and pathology of notch signalling system. J Cell Physiol. 207:300–308. 2006. View Article : Google Scholar : PubMed/NCBI
12	Lai EC: Notch signaling: control of cell communication and cell fate. Development. 131:965–973. 2004. View Article : Google Scholar : PubMed/NCBI
13	Artavanis-Tsakonas S, Rand MD and Lake RJ: Notch signaling: cell fate control and signal integration in development. Science. 284:7701999. View Article : Google Scholar : PubMed/NCBI
14	Greenwald I: LIN-12/Notch signaling: lessons from worms and flies. Genes Dev. 12:1751–1762. 1998. View Article : Google Scholar : PubMed/NCBI
15	Miele L, Miao H and Nickoloff BJ: NOTCH signaling as a novel cancer therapeutic target. Curr Cancer Drug Targets. 6:313–323. 2006. View Article : Google Scholar : PubMed/NCBI
16	Indraccolo S, Minuzzo S, Masiero M and Amadori A: Ligand-driven activation of the notch pathway in T-ALL and solid tumors: why Not(ch)? Cell Cycle. 9:80–85. 2010. View Article : Google Scholar : PubMed/NCBI
17	Park JT, Li M, Nakayama K, et al: Notch3 gene amplification in ovarian cancer. Cancer Res. 66:6312–6318. 2006. View Article : Google Scholar : PubMed/NCBI
18	Yamaguchi N, Oyama T, Ito E, et al: NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells. Cancer Res. 68:1881–1888. 2008. View Article : Google Scholar : PubMed/NCBI
19	Serafin V, Persano L, Moserle L, et al: Notch3 signalling promotes tumour growth in colorectal cancer. J Pathol. 224:448–460. 2011. View Article : Google Scholar : PubMed/NCBI
20	Chen X, Stoeck A, Lee SJ, Shih Ie M, Wang MM and Wang TL: Jagged1 expression regulated by Notch3 and Wnt/beta-catenin signaling pathways in ovarian cancer. Oncotarget. 1:210–218. 2010.PubMed/NCBI
21	Rodilla V, Villanueva A, Obrador-Hevia A, et al: Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc Natl Acad Sci USA. 106:6315–6320. 2009. View Article : Google Scholar : PubMed/NCBI
22	Jundt F, Probsting KS, Anagnostopoulos I, et al: Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. Blood. 103:3511–3515. 2004. View Article : Google Scholar : PubMed/NCBI
23	Choi JH, Park JT, Davidson B, Morin PJ, Shih Ie M and Wang TL: Jagged-1 and Notch3 juxtacrine loop regulates ovarian tumor growth and adhesion. Cancer Res. 68:5716–5723. 2008. View Article : Google Scholar : PubMed/NCBI
24	Moreno CS, Evans CO, Zhan X, Okor M, Desiderio DM and Oyesiku NM: Novel molecular signaling and classification of human clinically nonfunctional pituitary adenomas identified by gene expression profiling and proteomic analyses. Cancer Res. 65:10214–10222. 2005. View Article : Google Scholar
25	Evans CO, Moreno CS, Zhan X, et al: Molecular pathogenesis of human prolactinomas identified by gene expression profiling, RT-qPCR, and proteomic analyses. Pituitary. 11:231–245. 2008. View Article : Google Scholar : PubMed/NCBI
26	Miao Z, Miao Y, Lin Y and Lu X: Overexpression of the Notch3 receptor in non-functioning pituitary tumours. J Clin Neurosci. 19:107–110. 2012. View Article : Google Scholar : PubMed/NCBI
27	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.
28	Konishi J, Yi F, Chen X, Vo H, Carbone DP and Dang TP: Notch3 cooperates with the EGFR pathway to modulate apoptosis through the induction of Bim. Oncogene. 29:589–596. 2010. View Article : Google Scholar : PubMed/NCBI
29	Haruki N, Kawaguchi KS, Eichenberger S, et al: Dominant-negative Notch3 receptor inhibits mitogen-activated protein kinase pathway and the growth of human lung cancers. Cancer Res. 65:3555–3561. 2005. View Article : Google Scholar : PubMed/NCBI
30	Ohashi S, Natsuizaka M, Yashiro-Ohtani Y, et al: NOTCH1 and NOTCH3 coordinate esophageal squamous differentiation through a CSL-dependent transcriptional network. Gastroenterology. 139:2113–2123. 2010. View Article : Google Scholar : PubMed/NCBI
31	Masieron M, Minuzzo S, Pusceddu I, et al: Notch3-mediated regulation of MKP-1 levels promotes survival of T acute lymphoblastic leukemia cells. Leukemia. 25:588–598. 2011. View Article : Google Scholar : PubMed/NCBI
32	Desiderio DM and Zhan X: The human pituitary proteome: the characterization of differentially expressed proteins in an adenoma compared to a control. Cell Mol Biol (Noisy-le-grand). 49:689–712. 2003.PubMed/NCBI
33	Goldberg LB, Aujla PK and Raetzman LT: Persistent expression of activated Notch inhibits corticotrope and melanotrope differentiation and results in dysfunction of the HPA axis. Dev Biol. 358:23–32. 2011. View Article : Google Scholar : PubMed/NCBI
34	Zhu X, Zhang J, Tollkuhn J, et al: Sustained Notch signaling in progenitors is required for sequential emergence of distinct cell lineages during organogenesis. Genes Dev. 20:2739–2753. 2006. View Article : Google Scholar : PubMed/NCBI
35	Dutta S, Dietrich JE, Westerfield M and Varga ZM: Notch signaling regulates endocrine cell specification in the zebrafish anterior pituitary. Dev Biol. 319:248–257. 2008. View Article : Google Scholar : PubMed/NCBI
36	Zeng Q, Li S, Chepeha DB, et al: Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell. 8:13–23. 2005. View Article : Google Scholar : PubMed/NCBI
37	Steg AD, Katre AA, Goodman B, et al: Targeting the notch ligand JAGGED1 in both tumor cells and stroma in ovarian cancer. Clin Cancer Res. 17:5674–5685. 2011. View Article : Google Scholar : PubMed/NCBI
38	Bellavia D, Campese AF, Alesse E, et al: Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice. EMBO J. 19:3337–3348. 2000. View Article : Google Scholar : PubMed/NCBI
39	Vacca A, Felli MP, Palermo R, et al: Notch3 and pre-TCR interaction unveils distinct NF-kappaB pathways in T-cell development and leukemia. EMBO J. 25:1000–1008. 2006. View Article : Google Scholar : PubMed/NCBI
40	Monahan P, Rybak S and Raetzman LT: The notch target gene HES1 regulates cell cycle inhibitor expression in the developing pituitary. Endocrinology. 150:4386–4394. 2009. View Article : Google Scholar : PubMed/NCBI
41	Kita A, Imayoshi I, Hojo M, et al: Hes1 and Hes5 control the progenitor pool, intermediate lobe specification, and posterior lobe formation in the pituitary development. Mol Endocrinol. 21:1458–1466. 2007. View Article : Google Scholar : PubMed/NCBI
42	Jordan S, Lidhar K, Korbonits M, Lowe DG and Grossman AB: Cyclin D and cyclin E expression in normal and adenomatous pituitary. Eur J Endocrinol. 143:R1–R6. 2000. View Article : Google Scholar : PubMed/NCBI
43	Shih IeM and Wang TL: Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res. 67:1879–1882. 2007. View Article : Google Scholar : PubMed/NCBI
44	Tammam J, Ware C, Efferson C, et al: Down-regulation of the Notch pathway mediated by a gamma-secretase inhibitor induces anti-tumour effects in mouse models of T-cell leukaemia. Br J Pharmacol. 158:1183–1195. 2009. View Article : Google Scholar : PubMed/NCBI
45	Konishi J, Kawaguchi KS, Vo H, et al: Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers. Cancer Res. 67:8051–8057. 2007. View Article : Google Scholar : PubMed/NCBI
46	Kondratyev M, Kreso A, Hallett RM, et al: Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer. Oncogene. 31:93–103. 2012. View Article : Google Scholar : PubMed/NCBI
47	Ramakrishnan V, Ansell S, Haug J, et al: MRK003, a γ-secretase inhibitor exhibits promising in vitro pre-clinical activity in multiple myeloma and non-Hodgkin’s lymphoma. Leukemia. 26:340–348. 2012.