Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo
Wnt inhibitory factor 1 induces apoptosis and inhibits cervical cancer growth, invasion and angiogenesis in vivo
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DOI：
10.1038/onc.2011.455
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发表时间：
2012-05-01
期刊：
影响因子：
8
通讯作者：
Queimado, L.
中科院分区：
文献类型：
--
作者：
Ramachandran, I.;Thavathiru, E.;Queimado, L.
无翅型（Wnt）β-连环蛋白信号传导的激活在人宫颈癌中广泛存在。然而，Wnt激活的潜在机制和Wnt抑制的治疗潜力在很大程度上仍然未知。在这里，我们证明了Wnt抑制因子1（WIF 1），分泌的Wnt拮抗剂，在所有人原发性宫颈肿瘤和细胞系分析下调。我们的数据显示，WIF 1下调是由于启动子甲基化，是宫颈癌发生的早期事件。5-氮杂-2 '-脱氧胞苷处理或WIF 1基因转移后WIF 1重新表达可诱导显着的细胞凋亡和G（2）/M阻滞，并抑制体外宫颈癌细胞增殖。与此一致，用瘤周WIF 1基因转移治疗已建立的小鼠肿瘤异种移植物导致癌症生长和侵袭的显著抑制。WIF 1治疗导致细胞内WNT 1和TCF-4蛋白的显着减少，揭示了新的Wnt调节机制。因此，WIF 1导致β-连环蛋白的主要细胞再分布和肿瘤细胞中Wnt/β-连环蛋白途径的显著抑制，如Wnt/β-连环蛋白转录靶基因（E-钙粘蛋白、c-Myc、细胞周期蛋白D1、CD 44和VEGF）表达的显著逆转所证明的。因此，WIF 1抑制肿瘤进展和转移中的多个关键事件，如细胞增殖、血管生成和侵袭。此外，WIF 1调节特异性抗凋亡和凋亡蛋白的表达，从而在体内诱导显著的凋亡。我们的研究结果首次表明，WIF 1下调表观遗传基因沉默是一个重要的机制Wnt激活宫颈癌的发生。主要的临床相关性，我们表明，肿瘤周围的WIF 1基因转移不仅减少癌症的生长，而且在良好的肿瘤侵袭。因此，我们的数据为WIF 1在宫颈癌进展中的作用提供了新的机制见解，以及WIF 1作为宫颈癌治疗中有效药物靶标的重要临床前验证。Oncogene（2012）31，2725-2737; doi：10.1038/onc.2011.455; 2011年10月17日在线发表
activation of Wingless-type (Wnt)beta-catenin signaling is widespread in human cervical cancer. However, the underlying mechanisms of Wnt activation and the therapeutic potential of Wnt inhibition remain largely unknown. Here, we demonstrate that the Wnt inhibitory factor 1 (WIF1), a secreted Wnt antagonist, is downregulated in all human primary cervical tumors and cell lines analyzed. Our data reveal that WIF1 downregulation occurs due to promoter hypermethylation and is an early event in cervical oncogenesis. WIF1 re-expression upon 5-aza-2'-deoxycytidine treatment or WIF1 gene transfer induces significant apoptosis and G(2)/M arrest, and inhibits cervical cancer cell proliferation in vitro. Consistent with this, treatment of established mice tumor xenografts with peritumoral WIF1 gene transfer results in a significant inhibition of cancer growth and invasion. WIF1 treatment causes a significant decrease in intracellular WNT1 and TCF-4 proteins revealing novel Wnt-regulatory mechanisms. Thus, WIF1 causes a major cellular re-distribution of beta-catenin and a significant inhibition of the Wnt/beta-catenin pathway in tumor cells, as documented by a remarkable reversion in the expression of Wnt/beta-catenin transcriptional target genes (E-cadherin, c-Myc, cyclin D1, CD44 and VEGF). Consequently, multiple critical events in tumor progression and metastasis such as cell proliferation, angiogenesis and invasion were inhibited by WIF1. In addition, WIF1 modulated the expression of specific anti-apoptotic and apoptotic proteins, thereby inducing significant apoptosis in vivo. Our findings demonstrate for the first time that WIF1 downregulation by epigenetic gene silencing is an important mechanism of Wnt activation in cervical oncogenesis. Of major clinical relevance, we show that peritumoral WIF1 gene transfer reduces not only cancer growth but also invasion in well-established tumors. Therefore, our data provide novel mechanistic insights into the role of WIF1 in cervical cancer progression, and the important preclinical validation of WIF1 as a potent drug target in cervical cancer treatment. Oncogene (2012) 31, 2725-2737; doi: 10.1038/onc.2011.455; published online 17 October 2011