Antitumor activity of cell-permeable RUNX3 protein in gastric cancer cells.
Antitumor activity of cell-permeable RUNX3 protein in gastric cancer cells.
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DOI：
10.1158/1078-0432.ccr-12-2692
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发表时间：
2013-02-01
期刊：
影响因子：
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通讯作者：
Jo D
中科院分区：
文献类型：
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作者：
Lim J;Duong T;Do N;Do P;Kim J;Kim H;El-Rifai W;Ruley HE;Jo D
胃癌是全球癌症死亡的主要原因。有限的治疗选择突显了了解导致疾病的分子变化并在此基础上开发治疗方法的必要性。本研究的目的是开发细胞可穿透(CP-)形式的矮小相关转录因子3，RUNX3-与胃癌和其他上皮性癌症有关的候选肿瘤抑制因子-RUNX3，以研究RUNX3在胃癌治疗中的治疗潜力。我们开发了新的大分子转导结构域(MTD)，它被测试了促进哺乳动物细胞和组织摄取蛋白质的能力，并用于将具有生物活性的RUNX3运送到人胃癌细胞。在NCI-N87人肿瘤移植瘤动物模型上检测了CP-RUNX3的治疗潜力。含有疏水性MTDS的RUNX3融合蛋白HM57R和HM85R进入胃癌细胞，抑制细胞表型(如细胞周期进展、损伤单层愈合和存活)，并诱导生物标记物表达的变化(如p21Waf1和血管内皮生长因子)，与先前描述的RUNX3对转化生长因子-β信号转导的影响一致。CP-RUNX3对人胃癌皮下移植瘤的生长也有抑制作用。治疗反应与增强肿瘤细胞系中RUNX3基因表达的研究相当；然而，当局部给药时，该蛋白最活跃，而不是全身给药(即静脉注射)。这些结果进一步证明RUNX3可以作为一种肿瘤抑制因子发挥作用，并提示实用的增强RUNX3功能的方法可能在某些类型的胃癌的治疗中有用。
Gastric cancer is a leading cause of cancer death worldwide. Limited therapeutic options highlight the need to understand the molecular changes responsible for the disease and to develop therapies based on this understanding. The goal of this study was to develop cell-permeable (CP-) forms of the RUNT-related transcription factor 3, RUNX3-a candidate tumor suppressor implicated in gastric and other epithelial cancers-to study the therapeutic potential of RUNX3 in the treatment of gastric cancer. We developed novel macromolecule transduction domains (MTD) which were tested for the ability to promote protein uptake by mammalian cells and tissues and used to deliver of biologically active RUNX3 into human gastric cancer cells. The therapeutic potential CP-RUNX3 was tested in the NCI-N87 human tumor xenograft animal model. RUNX3 fusion proteins, HM57R and HM85R, containing hydrophobic MTDs enter gastric cancer cells and suppress cell phenotypes (e.g., cell-cycle progression, wounded monolayer healing, and survival) and induce changes in biomarker expression (e.g., p21Waf1 and VEGF) consistent with previously described effects of RUNX3 on TGF-β signaling. CP-RUNX3 also suppressed the growth of subcutaneous human gastric tumor xenografts. The therapeutic response was comparable with studies augmenting RUNX3 gene expression in tumor cell lines; however, the protein was most active when administered locally, rather than systemically (i.e., intravenously). These results provide further evidence that RUNX3 can function as a tumor suppressor and suggest that practical methods to augment RUNX3 function could be useful in treating of some types of gastric cancer.