Overexpression of SnoN/SkiL, amplified at the 3q26.2 locus, in ovarian cancers: A role in ovarian pathogenesis
Overexpression of SnoN/SkiL, amplified at the 3q26.2 locus, in ovarian cancers: A role in ovarian pathogenesis
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DOI：
10.1016/j.molonc.2008.05.001
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发表时间：
2008-08-01
影响因子：
6.6
通讯作者：
Mills, Gordon B.
中科院分区：
文献类型：
--
作者：
Nanjundan, Meera;Cheng, Kwai Wa;Mills, Gordon B.
High-resolution array comparative genomic hybridization of 235 serous epithelial ovarian cancers demonstrated a regional increase at 3q26.2 encompassing SnoN/SkiL, a coregulator of SMAD/TGF beta signaling. SnoN RNA transcripts were elevated in similar to 80% of advanced stage serous epithelial ovarian cancers. In both immortalized normal (TIOSE) and ovarian carcinoma cell lines (OVCA), SnoN RNA levels were increased by TGF beta stimulation and altered by LY294002 and JNK II inhibitor treatment suggesting that the PI3K and JNK signaling pathways may regulate TGFP-induced increases in SnoN RNA. In TIOSE, SnoN protein levels were reduced 15 min post TGF beta-stimulation, likely by proteosome-mediated degradation. In contrast, in OVCA, SnoN levels were elevated 3 h post-stimulation potentially as a result of inhibition of the proteosome. To elucidate the role of SnoN in ovarian tumorigenesis, we explored the effects of both increasing and decreasing SnoN levels. In both TIOSE and OVCA, SnoN siRNA decreased cell growth between 20 and 50% concurrent with increased p21 levels. In TIOSE, transient expression of SnoN repressed TGF beta induction of PAI-1 promoters with little effect on the p21 promoter or resultant cell growth. In contrast to the effects of transient expression, stable expression of SnoN in TIOSE led to growth arrest through induction of senescence. Collectively, these results implicate SnoN levels in multiple roles during ovarian carcinogenesis: promoting cellular proliferation in ovarian cancer cells and as a positive mediator of cell cycle arrest and senescence in non-transformed ovarian epithelial cells. (C) 2008 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
