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

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

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 15 min post TGFβ-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 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.

Original languageEnglish (US)
Pages (from-to)164-181
Number of pages18
JournalMolecular Oncology
Volume2
Issue number2
DOIs
StatePublished - Aug 2008
Externally publishedYes

Fingerprint

Ovarian Neoplasms
RNA
Carcinogenesis
Growth
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Comparative Genomic Hybridization
MAP Kinase Signaling System
Cell Aging
Plasminogen Activator Inhibitor 1
Cell Cycle Checkpoints
Phosphatidylinositol 3-Kinases
Small Interfering RNA
Epithelial Cells
Cell Proliferation
Carcinoma
Cell Line
Proteins
Ovarian epithelial cancer

Keywords

  • 3q26.2 amplicon
  • Growth arrest
  • Ovarian cancers
  • p21
  • Senescence
  • SnoN/SkiL

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

Cite this

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; Mills, Gordon.

In: Molecular Oncology, Vol. 2, No. 2, 08.2008, p. 164-181.

Research output: Contribution to journalArticle

Nanjundan, M, Cheng, KW, Zhang, F, Lahad, J, Kuo, WL, Schmandt, R, Smith-McCune, K, Fishman, D, Gray, J & Mills, G 2008, 'Overexpression of SnoN/SkiL, amplified at the 3q26.2 locus, in ovarian cancers: A role in ovarian pathogenesis', Molecular Oncology, vol. 2, no. 2, pp. 164-181. https://doi.org/10.1016/j.molonc.2008.05.001
Nanjundan, Meera ; Cheng, Kwai Wa ; Zhang, Fan ; Lahad, John ; Kuo, Wen Lin ; Schmandt, Rosemarie ; Smith-McCune, Karen ; Fishman, David ; Gray, Joe ; Mills, Gordon. / Overexpression of SnoN/SkiL, amplified at the 3q26.2 locus, in ovarian cancers : A role in ovarian pathogenesis. In: Molecular Oncology. 2008 ; Vol. 2, No. 2. pp. 164-181.
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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 15 min post TGFβ-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 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.",
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AU - Zhang, Fan

AU - Lahad, John

AU - Kuo, Wen Lin

AU - Schmandt, Rosemarie

AU - Smith-McCune, Karen

AU - Fishman, David

AU - Gray, Joe

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