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Wnt pathway inhibitors are strongly down-regulated in pituitary tumors
被引:86
作者:
Elston, Marianne S.
[3
]
Gill, Anthony J.
[1
,5
]
Conaglen, John V.
[7
]
Clarkson, Adele
[1
,5
]
Shaw, Janet M.
[3
]
Law, Andrew J. J.
[8
]
Cook, Raymond J.
[2
,4
]
Little, Nicholas S.
[2
,4
]
Clifton-Bligh, Roderick J.
[3
]
Robinson, Bruce G.
[6
]
McDonald, Kerrie L.
[3
]
机构:
[1] Royal N Shore Hosp, Dept Anat Pathol, Sydney, NSW 2065, Australia
[2] Royal N Shore Hosp, Dept Neurosurg, Sydney, NSW 2065, Australia
[3] Royal N Shore Hosp, Kolling Inst Med Res, Canc Genet Unit, Sydney, NSW 2065, Australia
[4] N Shore Private Hosp, Dept Neurosurg, Sydney, NSW 2065, Australia
[5] Univ Sydney, Sydney, NSW 2006, Australia
[6] Fac Med, Sydney, NSW 2006, Australia
[7] Waikato Hosp, Dept Endocrinol, Waikato 3204, New Zealand
[8] Auckland City Hosp, Dept Neurosurg, Auckland 1023, New Zealand
关键词:
D O I:
10.1210/en.2007-0542
中图分类号:
R5 [内科学];
学科分类号:
1002 ;
100201 ;
摘要:
The etiology of sporadic pituitary tumors is currently unknown. The Writ pathways have been implicated in the pathogenesis of a variety of human tumors, but the role of these pathways in pituitary tumors is unclear. Microarray analysis using the Affymetrix HG U133 plus 2.0 GeneChips identified four secreted frizzled-related protein (sFRP) family members of Writ pathway inhibitors that were differentially expressed in both nonfunctioning and clinically functioning pituitary tumors (n = 20) compared with normal pituitary controls (n = 3). Reduced tumor expression of Writ inhibitory factor-1 (WIF1), sFRP2, and sFRP4 mRNA was confirmed by real-time quantitative RT-PCR (P < 0.001 and P = 0.002 and 0.013, respectively) in all pituitary subtypes. Hypermethylation of the WIF1 promoter was present in 88% of the pituitary tumors (n = 41). Seventy-six percent of pituitary tumors demonstrated absent or weak cytoplasmic WIF1 staining by immunohistochemistry (n = 41), although preserved staining was seen in some functioning tumors, with strong staining in 92% of normal pituitary controls (n = 13). The Writ pathway target gene cyclin D1 was found to be up-regulated specifically in the nonfunctioning pituitary tumors compared with controls at,; both mRNA and protein level, supportive of activation of the Wnt-beta-catenin pathway. Nuclear accumulation of P-catenin, however, was not observed in any pituitary tumors (n = 70). By transfecting GH3 cells with WIF1, decreased,cell proliferation and colony formation was observed compared with empty vector controls. In conclusion, our data suggest that WIF1 may be a tumor suppressor, specifically in nonfunctioning pituitary tumors, and that the Writ pathways are important in pituitary tumorigenesis.
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页码:1235 / 1242
页数:8
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