TGF-beta induces serous borderline ovarian tumor cell invasion by activating EMT but triggers apoptosis in low-grade serous ovarian carcinoma cells.
TGF-beta induces serous borderline ovarian tumor cell invasion by activating EMT but triggers apoptosis in low-grade serous ovarian carcinoma cells.
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DOI：
10.1371/journal.pone.0042436
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Leung PC
中科院分区：
文献类型：
--
作者：
Cheng JC;Auersperg N;Leung PC
转化生长因子-β (TGF-β) 诱导卵巢表面上皮 (OSE) 细胞凋亡。然而，高级别浆液性卵巢癌 (HGC) 对 TGF-β 的抑制功能无效； TGF-β 通过上皮间质转化 (EMT) 激活上调它们的侵袭性。浆液性交界性卵巢肿瘤 (SBOT) 已被认为是导致侵袭性低级别浆液性癌 (LGC) 的独特实体，其预后相对较差且与 HGC 无关。虽然尚不完全了解 TGF-β 如何在 OSE 细胞及其恶性衍生物 HGC 中发挥不同的作用，但其在 SBOT 和 LGC 中的作用仍然未知。在这里，我们展示了 TGF-β 对培养的 SBOT3.1 和 LGC 衍生的 MPSC1 细胞的影响，这些细胞表达 TGF-β I 型和 II 型受体。 TGF-β处理诱导SBOT3.1细胞的侵袭性，但降低MPSC1细胞的侵袭性。通过裂解 caspase-3 和台盼蓝排除试验评估细胞凋亡分析，发现 MPSC1 细胞中存在 TGF-β 诱导的细胞凋亡，但 SBOT3.1 细胞中则不然。 TGF-β 对 LGC 细胞的促凋亡作用在另一种永生化 LGC 细胞系 ILGC 中得到证实。 TGF-β 处理导致 Smad3 激活，但不激活 Smad2。特异性TβRI抑制剂SB431542和TβRI siRNA消除了TGF-β诱导的SBOT3.1侵袭，并阻止了TGF-β诱导的MPSC1细胞凋亡。在 SBOT3.1 细胞中，TGF-β 下调 E-钙粘蛋白，同时上调 N-钙粘蛋白。 TGF-β 上调 E-cadherin、Snail、Slug、Twist 和 ZEB1 转录抑制因子的表达。相反，与SB431542和通过siRNA去除TβRI的共同处理消除了TGF-β对相对钙粘蛋白表达水平以及Snail、Slug、Twist和ZEB1表达水平的影响。本研究证明了 TGF-β 的双重功能：通过 EMT 激活诱导 SBOT 细胞侵袭，并促进 LGC 细胞凋亡。
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 TβRI inhibitor SB431542 and TβRI 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 TβRI 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.