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三部分基序包含 28 个抑制物的敲除通过下调 Wnt/β-连环蛋白信号通路抑制卵巢癌细胞的迁移、侵袭和上皮-间充质转化。

Knockdown of Tripartite Motif Containing 28 suppresses the migration, invasion and epithelial-mesenchymal transition in ovarian carcinoma cells through down-regulation of Wnt/β-catenin signaling pathway.

出版信息

Neoplasma. 2017;64(6):893-900. doi: 10.4149/neo_2017_611.

DOI:10.4149/neo_2017_611
PMID:28895414
Abstract

Tripartite motif containing 28 (TRIM28) is a transcriptional corepressor of Kruppel-associated box zinc finger protein, which has been reported to participate in carcinogenesis. Nonetheless, whether TRIM28 plays a role in the metastasis of ovarian carcinoma (OC) is unclear and requires further investigation. In this study, two OC cell lines (A2780 and OVCAR-3) with stable low expression of TRIM28 were established via RNA interference. We found that the migratory and invasive ability of TRIM28-silenced OC cells significantly decreased. The expression and activity of matrix metallopeptidase (MMP)-2 and MMP-9 in these OC cells were inhibited. The TRIM28 shRNA also suppressed the epithelial-mesenchymal transition (EMT) of OC cells as evidenced by the up-regulated E-cadherin and the downregulated Vimentin and N-cadherin. Additionally, the Wnt/β-catenin signaling pathway was suppressed in TRIM28-silenced OC cells: the activity of β-catenin was inhibited, the expression of total and nuclear β-catenin, Axin 2, T-cell factor 1 (TCF1) and lymphoid enhancer binding factor 1 (LEF1) were decreased, whereas the phosphorylation of β-catenin at Ser33/37 was enhanced. Further, re-expression of active β-catenin in TRIM28-silenced OC cells partly restored their metastasis in vitro. Taken together, our study demonstrates a contributory role of TRIM28 in OC metastasis in vitro, suggesting TRIM28 as a novel therapeutic target for this malignant tumor.

摘要

三结构域蛋白 28(TRIM28)是一种与 Kruppel 相关盒锌指蛋白的转录共抑制因子,据报道其参与了癌症的发生。然而,TRIM28 是否在卵巢癌(OC)的转移中发挥作用尚不清楚,需要进一步研究。在这项研究中,通过 RNA 干扰建立了两种稳定低表达 TRIM28 的 OC 细胞系(A2780 和 OVCAR-3)。我们发现,沉默 TRIM28 的 OC 细胞的迁移和侵袭能力显著降低。这些 OC 细胞中基质金属蛋白酶(MMP)-2 和 MMP-9 的表达和活性受到抑制。TRIM28 shRNA 还抑制了 OC 细胞的上皮-间充质转化(EMT),表现为 E-钙黏蛋白上调,波形蛋白和 N-钙黏蛋白下调。此外,在沉默 TRIM28 的 OC 细胞中抑制了 Wnt/β-catenin 信号通路:β-连环蛋白的活性受到抑制,总蛋白和核蛋白β-catenin、轴蛋白 2、T 细胞因子 1(TCF1)和淋巴增强结合因子 1(LEF1)的表达减少,而β-连环蛋白在 Ser33/37 位点的磷酸化增强。进一步,在沉默 TRIM28 的 OC 细胞中重新表达活性β-catenin 部分恢复了其体外转移能力。总之,我们的研究表明 TRIM28 在 OC 体外转移中起促进作用,提示 TRIM28 可能成为这种恶性肿瘤的新治疗靶点。

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