Downregulation of metastasis suppressor genes in malignant pheochromocytoma.
There is no reliable method currently available to predict malignant potential of pheochromocytoma based on conventional histology or genetic, molecular or immunohistochemical markers. Metastasis suppressor genes affect the spread of several cancers and, therefore, may provide promise as prognostic markers or therapeutic targets for malignant pheochromocytoma. We hypothesized that the downregulation of metastasis suppressor genes in malignant pheochromocytoma may play a role in malignant behavior. We applied quantitative real-time polymerase chain reaction (QRT-PCR) to 11 metastasis suppressor genes. These genes are known to be involved in the regulation of important cancer-related cellular events, such as cell growth regulation and apoptosis (nm23-H1, TIMP-1, TIMP-2, TIMP-3, TIMP-4, TXNIP and CRSP-3), cell-cell communication (BRMS-1), invasion (CRMP-1) and cell adhesion (E-Cad and KiSS1). The study included 15 benign and 10 malignant pheochromocytomas. Six metastasis suppressor genes (nm23-H1, TIMP-4, BRMS-1, TXNIP, CRSP-3 and E-Cad) were downregulated significantly in malignant compared to benign pheochromocytoma (p < 0.05, Mann-Whitney U-test). We applied a non-linear rule using median malignant value (MMV) as a threshold to use metastasis suppressor genes to distinguish malignant from benign samples. After cross-validation, the non-linear rule produced no errors in 10 malignant samples and 3 errors in the 15 benign samples, with an overall error rate of 12%. These results suggest that downregulation of metastasis suppressor genes reflect malignant pheochromocytoma with a high degree of sensitivity. Thus, we conclude that altered function of these metastasis suppressor gene pathways may play an important role in the malignant behavior of pheochromocytoma.
Ohta
Shoichiro
S
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892-1583, USA.
Lai
Edwin W
EW
Pang
Alan L Y
AL
Brouwers
Frederieke M
FM
Chan
Wai-Yee
WY
Eisenhofer
Graeme
G
de Krijger
Ronald
R
Ksinantova
Lucia
L
Breza
Jan
J
Blazicek
Pavel
P
Kvetnansky
Richard
R
Wesley
Robert A
RA
Pacak
Karel
K
D000310:Adrenal Gland Neoplasms / Q000378:metabolism; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D056892:Mediator Complex; D008875:Middle Aged; D054778:NM23 Nucleoside Diphosphate Kinases; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism; D010673:Pheochromocytoma / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D000097792:Tissue Inhibitor of Metalloproteinase-4
D014408:Biomarkers, Tumor; D015820:Cadherins; D056892:Mediator Complex; D054778:NM23 Nucleoside Diphosphate Kinases; D009701:Nucleoside-Diphosphate Kinase; D019714:Tissue Inhibitor of Metalloproteinases; D015534:Trans-Activators; D000097792:Tissue Inhibitor of Metalloproteinase-4; C492159:MED23 protein, human; C517938:NME1 protein, human