PDF(Pubmed)
Abstract：
The dynamic crosstalk between tumor and stromal cells is a major determinant of cancer aggressiveness. The tumor-suppressor DAB2IP (Disabled homolog 2 interacting protein) plays an important role in this context, since it modulates cell responses to multiple extracellular inputs, including inflammatory cytokines and growth factors. DAB2IP is a RasGAP and negatively controls Ras-dependent mitogenic signals. In addition, it modulates other major oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptor signaling. In line with its tumor-suppressive role, DAB2IP is frequently inactivated in cancer by transcriptional and post-transcriptional mechanisms, including promoter methylation, microRNA-mediated downregulation, and protein-protein interactions. Intriguingly, some observations suggest that downregulation of DAB2IP in cells of the tumor stroma could foster establishment of a pro-metastatic microenvironment. This review summarizes recent insights into the tumor-suppressive functions of DAB2IP and the consequences of its inactivation in cancer. In particular, we explore potential approaches aimed at reactivating DAB2IP, or augmenting its expression levels, as a novel strategy in cancer treatment. We suggest that reactivation or upregulation of DAB2IP would concurrently attenuate multiple oncogenic pathways in both cancer cells and the tumor microenvironment, with implications for improved treatment of a broad spectrum of tumors.
摘要：
肿瘤和基质细胞之间的动态串扰是癌症侵袭性的主要决定因素。肿瘤抑制因子DAB2IP（残疾同源物2相互作用蛋白）在这种情况下发挥重要作用，因为它调节细胞对多种细胞外输入的反应，包括炎症细胞因子和生长因子。DAB2IP是RasGAP并且负控制Ras依赖性有丝分裂信号。此外,它调节其他主要的致癌途径，包括TNFα/NF-κB，WNT/β-连环蛋白，PI3K/AKT,和雄激素受体信号。根据其肿瘤抑制作用，DAB2IP在癌症中经常通过转录和转录后机制失活，包括启动子甲基化，microRNA介导的下调，和蛋白质-蛋白质相互作用。有趣的是，一些观察结果表明,DAB2IP在肿瘤基质细胞中的下调可能促进促转移微环境的建立.这篇综述总结了有关DAB2IP的肿瘤抑制功能及其在癌症中失活的后果的最新见解。特别是,我们探索了旨在重新激活DAB2IP的潜在方法，或者增加它的表达水平，作为癌症治疗的新策略。我们建议DAB2IP的再激活或上调将同时减弱癌细胞和肿瘤微环境中的多种致癌途径。对改善广谱肿瘤的治疗有意义。
