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- Title
TGF-Beta Induces Serous Borderline Ovarian Tumor Cell Invasion by Activating EMT but Triggers Apoptosis in Low-Grade Serous Ovarian Carcinoma Cells.
- Authors
Jung-Chien Cheng; Auersperg, Nelly; Leung, Peter C. K.; Srivastava, Rakesh K.
- Abstract
Apoptosis in ovarian surface epithelial (OSE) cells is induced by transforming growth factor-beta ( TGF-β). However, high-grade serous ovarian carcinomas (HGC) are refractory to the inhibitory functions of TGF- β; their invasiveness is up-regulated by TGF-β through epithelial- mesenchymal transition (EMT) activation. Serous borderline ovarian tumors (SBOT) have been recognized as distinct entities that give rise to invasive low-grade serous carcinomas (LGC), which have a relatively poor prognosis and are unrelated to HGC. While it is not fully understood how TGF-β plays disparate roles in OSE cells and its malignant derivative HGC, its role in SBOT and LGC remains unknown. Here we demonstrate the effects of TGF-β on cultured SBOT3.1 and LGC-derived MPSC1 cells, which express TGF-β type I and type II receptors. TGF-β treatment induced the invasiveness of SBOT3.1 cells but reduced the invasiveness of MPSC1 cells. The analysis of apoptosis, which was assessed by cleaved caspase-3 and trypan blue exclusion assay, revealed TGF-β-induced apoptosis in MPSC1, but not SBOT3.1 cells. The pro- apoptotic effect of TGF-β on LGC cells was confirmed in another immortalized LGC cell line ILGC. TGF-β treatment led to the activation of Smad3 but not Smad2. The specific TbRI inhibitor SB431542 and TbRI siRNA abolished the SBOT3.1 invasion induced by TGF-β, and it prevented TGF- β-induced apoptosis in MPSC1 cells. In SBOT3.1 cells, TGF-β down- regulated E-cadherin and concurrently up-regulated N-cadherin. TGF-β up- regulated the expression of the transcriptional repressors of E-cadherin, Snail, Slug, Twist and ZEB1. In contrast, co-treatment with SB431542 and TbRI depletion by siRNA abolished the effects of TGF-β on the relative cadherin expression levels and that of Snail, Slug, Twist and ZEB1 as well. This study demonstrates dual TGF-β functions: the induction of SBOT cell invasion by EMT activation and apoptosis promotion in LGC cells.
- Subjects
APOPTOSIS; TRANSFORMING growth factors-beta; CANCER cells; CADHERINS; CELL death; CELLS
- Publication
PLoS ONE, 2012, Vol 7, Issue 8, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0042436