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Department of Molecular Medicine and Surgery, CMM L8:01, Karolinska Institutet, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden,
¹ Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden,
² Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden,
³ Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden,
⁴ Department of Cell and Cancer Biology, National Cancer Institute, Rockville, Maryland, USA and
⁵ Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden

(Requests for offprints should be addressed to J Geli; Email: janos.geli{at}ki.se)

NORE1A (RASSF5) and RASSF1A are newly described Ras effectors with tumour suppressor functions. Both molecules are frequently inactivated in various cancers. In this study, we aimed to explore the potential involvement of NORE1A and RASSF1A in pheochromocytoma and abdominal paraganglioma tumorigenesis. A panel of 54 primary tumours was analysed for NORE1A and RASSF1A mRNA expression by TaqMan quantitative RT-PCR. Furthermore, NORE1A and RASSF1A promoter methylation was assessed by combined bisulphite restriction endonuclease assay and methylation-sensitive Pyrosequencing respectively. The anti-tumorigenic role of NORE1A was functionally investigated in Nore1A-transfected PC12 rat pheochromocytoma cells by fluorescent inhibition of caspase activity and soft agar assays. Significantly suppressed NORE1A and RASSF1A mRNA levels were detected in primary tumours compared with normal adrenal medulla (P<0.001). Methylation of the NORE1A promoter was not observed in primary tumours. On the other hand, 9% (5/54) of the primary tumours examined showed RASSF1A promoter methylation greater than 20% as detected by Pyrosequencing. Methylation of the RASSF1A promoter was significantly associated with malignant behaviour (P<0.05). Transient expression of Nore1a resulted in enhanced apoptosis and impaired colony formation in soft agar. Our study provides evidence that NORE1A and RASSF1A are frequently suppressed in pheochromocytoma and abdominal paraganglioma. Silencing of NORE1A contributes to the transformed phenotype in these tumours.

This article has been cited by other articles:

				N B Kiss, J Geli, F Lundberg, C Avci, D Velazquez-Fernandez, J Hashemi, G Weber, A Hoog, T J Ekstrom, M Backdahl, et al. Methylation of the p16INK4A promoter is associated with malignant behavior in abdominal extra-adrenal paragangliomas but not pheochromocytomas Endocr. Relat. Cancer, June 1, 2008; 15(2): 609 - 621. [Abstract] [Full Text] [PDF]

				J. Geli, N. Kiss, M. Karimi, J.-J. Lee, M. Backdahl, T. J. Ekstrom, and C. Larsson Global and Regional CpG Methylation in Pheochromocytomas and Abdominal Paragangliomas: Association to Malignant Behavior Clin. Cancer Res., May 1, 2008; 14(9): 2551 - 2559. [Abstract] [Full Text] [PDF]