Overexpression of SnoN/SkiL, amplified at the 3q26.2 locus, in ovarian cancers: A role in ovarian pathogenesis

Nanjundan, Meera; Cheng, Kwai Wa; Zhang, Fan; Lahad, John; Kuo, Wen-Lin; Schmandt, Rosemarie; Smith-McCune, Karen; Fishman, David; Gray, Joe W.; Mills, Gordon B.

doi:10.1016/j.molonc.2008.05.001

« Previous Next »Molecular Oncology
Volume 2, Issue 2 , Pages 164-181, August 2008

Overexpression of SnoN/SkiL, amplified at the 3q26.2 locus, in ovarian cancers: A role in ovarian pathogenesis

Meera Nanjundan
- University of Texas, MD Anderson Cancer Center, Department of Systems Biology, 1515 Holcombe Boulevard, Box 950, Houston, TX, USA
- University of South Florida, Division of Cell, Microbiology, and Molecular Biology, 4202 East Fowler Avenue, SCA110, Tampa, FL, USA
- Corresponding author at: University of South Florida, Division of Cell, Microbiology, and Molecular Biology, 4202 East Fowler Avenue, SCA110, Tampa, FL 33620, USA. Tel.: +1 813 974 8133; fax: +1 813 974 1614.
Kwai Wa Cheng
- University of Texas, MD Anderson Cancer Center, Department of Systems Biology, 1515 Holcombe Boulevard, Box 950, Houston, TX, USA
Fan Zhang
- University of Texas, MD Anderson Cancer Center, Department of Systems Biology, 1515 Holcombe Boulevard, Box 950, Houston, TX, USA
John Lahad
- University of Texas, MD Anderson Cancer Center, Department of Systems Biology, 1515 Holcombe Boulevard, Box 950, Houston, TX, USA
Wen-Lin Kuo
- University of California San Francisco, Department of Laboratory Medicine and the Lawrence Berkeley National Laboratory, Berkeley, CA, USA
Rosemarie Schmandt
- Department of Gynecologic Oncology, MD Anderson Cancer Center, Houston, TX, USA
Karen Smith-McCune
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, CA, USA
David Fishman
- New York University, New York, NY, USA
Joe W. Gray
- University of California San Francisco, Department of Laboratory Medicine and the Lawrence Berkeley National Laboratory, Berkeley, CA, USA
Gordon B. Mills
- University of Texas, MD Anderson Cancer Center, Department of Systems Biology, 1515 Holcombe Boulevard, Box 950, Houston, TX, USA

Received 8 December 2007; received in revised form 1 May 2008; accepted 6 May 2008. published online 03 June 2008.

Abstract

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/TGFβ signaling. SnoN RNA transcripts were elevated in ∼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 TGFβ stimulation and altered by LY294002 and JNK II inhibitor treatment suggesting that the PI3K and JNK signaling pathways may regulate TGFβ-induced increases in SnoN RNA. In TIOSE, SnoN protein levels were reduced 15min post TGFβ-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 TGFβ 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.