Overexpression of SnoN/SkiL, amplified at the 3q26.2 locus, in ovarian cancers: a role in ovarian pathogenesis.
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/TGFbeta signaling. SnoN RNA transcripts were elevated in approximately 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 TGFbeta stimulation and altered by LY294002 and JNK II inhibitor treatment suggesting that the PI3K and JNK signaling pathways may regulate TGFbeta-induced increases in SnoN RNA. In TIOSE, SnoN protein levels were reduced 15min post TGFbeta-stimulation, likely by proteosome-mediated degradation. In contrast, in OVCA, SnoN levels were elevated 3h 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 TGFbeta 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.
Nanjundan
Meera
M
University of Texas, MD Anderson Cancer Center, Department of Systems Biology, 1515 Holcombe Boulevard, Box 950, Houston, TX, USA. mnanjund@cas.usf.edu
Cheng
Kwai Wa
KW
Zhang
Fan
F
Lahad
John
J
Kuo
Wen-Lin
WL
Schmandt
Rosemarie
R
Smith-McCune
Karen
K
Fishman
David
D
Gray
Joe W
JW
Mills
Gordon B
GB
D002453:Cell Cycle; D049109:Cell Proliferation; D016922:Cellular Senescence; D002893:Chromosomes, Human, Pair 3; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000209:etiology / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012334:RNA, Neoplasm / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm; C060615:SKIL protein, human; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases