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Comparative Study
. 2005 Sep 19;93(6):709-18.
doi: 10.1038/sj.bjc.6602719.

The Notch pathway in ovarian carcinomas and adenomas

O Hopfer  1 , D Zwahlen, M F Fey, S Aebi
Affiliations
Comparative Study

The Notch pathway in ovarian carcinomas and adenomas

O Hopfer et al. Br J Cancer. .

Abstract

Elements of the Notch pathway regulate differentiation; we investigated the expression of such elements in epithelial ovarian tumours. A total of 32 ovarian tumour samples (17 adenocarcinomas, three borderline tumours, 12 adenomas), two human ovarian cancer (A2780, OVCAR3), and one ovarian surface (IOSE 144) cell lines were analysed. The expression of Notch pathway elements was assessed by RT-PCR, real-time PCR (Notch 1), and by immunoblots (Notch 1 extracellular domain (EC), HES1). The proliferation and colony formation of A2780 cells were measured after stable transfection with activated Notch 1 (intracellular domain). Jagged 2, Delta-like-1, Manic Fringe, and TSL1 were expressed more frequently in adenocarcinomas whereas Deltex, Mastermind, and Radical Fringe were more frequent in adenomas. Quantitative PCR revealed decreased Notch 1 mRNA in ovarian adenocarcinomas compared with adenomas. The expression of Notch 1-EC protein was similar in benign and malignant tumours. HES1 protein was strongly expressed in 18/19 ovarian cancers and borderline tumours but not in adenomas. Transfecting A2780 cells with active Notch 1-IC resulted in a proliferative and colony formation advantage compared to mock transfected cells. Thus, Notch pathway elements are expressed in ovarian epithelial tumours and some of them are differentially expressed between adenomas and carcinomas. The Notch pathway could be a target for the development of therapies for ovarian cancer.

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Figures

Figure 1
Figure 1
Notch signal transduction elements: (1) Post-translational modification of precursor Notch-protein includes cleavage by a Furin-like convertase and glycosylation by members of the Fringe family (Radical (R), Manic (M), Lunatic (L)) in the trans-Golgi. (2) Adherence of Notch extracellular domain (ECN) with Notch intracellular domain (ICN) results in mature Notch heterodimers that are transferred to the cell membrane. Receptor interaction with ligands of the DSL-family (Delta, Serrate, Lag3) on neighbouring cells is modulated by Fringe modification of ECN. (3) E3 ubiquitin ligases (Mindbomb and Neutralised) control the turnover of DSL-ligands on signalling cells. (4) Ligand availability is further regulated by the metalloprotease Kuzbanian, shedding the extracellular domain of the transmembrane ligand protein. (5) Successful interaction of extracellular ligand regions with EGF-like repeats of ECN lead to (6) successive cleavage of Notch transmembrane domain by the disintegrin-metalloprotease tumour necrosis factor-α-converting enzyme (TACE) and the γ-secretase Presenillin. (7) ICN is released and translocates to the nucleus where it interacts with CSL1, replacing CSL-repressors (CoR) and forming a transcription complex with Mastermind-like factors (MAML) and transcriptional coactivators (CoA). (8) This transcriptional complex activates downstream target genes, including members of the Hairy enhancer of split (HES) family of transcriptional repressors (bHLH). (9) These HES proteins excert their function together with the Transducin-like enhancer of split (TSL) family of corepressors. Other target genes are tissue specific. (10) The half-life of ICN is regulated by E3 ligases of the Sel-10 family before proteasome degradation. (11) A CSL-independent Notch pathway involves the interaction of ICN with deltex, a cytosolic protein and positive regulator of Notch signalling. Adopted from Weng and Aster (2004).
Figure 2
Figure 2
RT–PCR results of representative examples (13=ovarian adenocarcinoma, 33=borderline tumour, 28=ovarian adenoma) for Notch pathway elements. 0, no signal detected. +, mRNA detected by RT–PCR. The results of duplicate experiments were identical.
Figure 3
Figure 3
Notch 1 mRNA real-time PCR, normalised for PBGD (arithmetic means of triplicate measurements).
Figure 4
Figure 4
Western blots for Notch 1 (full-length and extracellular domain (EC)) and HES-1 in ovarian adenocarcinomas, borderline tumours, adenomas and cell lines (ovarian adenocarcinoma A2780 and OVCAR-3, ovarian surface epithelium IOSE-144 and Hodgkin's lymphoma L540).
Figure 5
Figure 5
XTT-assay of A2780 human ovarian adenocarcinoma cells, stable transfections with hNotch 1-IC-HA (white circles) vs empty vector (black triangles) transfected.
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References

    1. Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284: 770–776. doi:10.1126/science.284.5415.770 - PubMed
    1. Bailey AM, Posakony JW (1995) Suppressor of hairless directly activates transcription of enhancer of split complex genes in response to Notch receptor activity. Genes Dev 9: 2609–2622 - PubMed
    1. Bash J, Zong WX, Banga S, Rivera A, Ballard DW, Ron Y, Gelinas C (1999) Rel/NF-kappaB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors. EMBO J 18: 2803–2811 - PMC - PubMed
    1. Bashey A, Gill R, Levi S, Farr CJ, Clutterbuck R, Millar JL, Pragnell IB, Marshall CJ (1992) Mutational activation of the N-ras oncogene assessed in primary clonogenic culture of acute myeloid leukemia (AML): implications for the role of N-ras mutation in AML pathogenesis. Blood 79: 981–989 - PubMed
    1. Chen Y, Fischer WH, Gill GN (1997) Regulation of the ERBB-2 promoter by RBP Jkappa and NOTCH. J Biol Chem 272: 14110–14114 - PubMed

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