microRNA分子参与肿瘤细胞上皮-间质转化过程中鲁棒性维持的分子机制

生物鲁棒性是生物体在内外界环境变化时维持其结构和功能稳定的一种特性，miRNA分子作为基因表达的精细调控者参与维持生物鲁棒性。我们分析了EGF或TGF-β诱导鼻咽癌细胞发生上皮-间质转化(EMT)时mRNA和miRNA表达谱变化，构建了miRNA参与维持EMT过程中鲁棒性的几个重要反馈环路。发现EMT过程中表达上调的miR-505、-1207-5p能抑制癌细胞迁移和侵袭能力，负调控EMT，维持系统鲁棒性。本项目中我们拟系统鉴定miR-505和miR-1207-5p在EMT过程中的靶基因；分析它们抑制EMT的机制是否与TGF-β和Wnt/β-catenin通路相关；它们对TGF-β诱导的"EMT-凋亡转换"的调控；以及它们在肿瘤微环境中如何发挥作用。这些研究将有助于更好理解EMT过程的鲁棒性，以及miRNA调控肿瘤侵袭转移的分子机制，为肿瘤转移的防治提供新的靶点。

Biological robustness is a system property to keep a stability of live-body structure and function as uncertainty factor from external and internal variety disturbs it. Biological systems use a variety of mechanisms to maintain their functions in the face of environmental and genetic perturbations. Increasing evidence suggests that, among their roles as posttranscriptional repressors of gene expression, microRNAs (miRNAs) help to confer robustness to biological processes by reinforcing transcriptional programs and attenuating aberrant transcripts. These activities have important consequences for normal development and physiology, disease, and evolution. The majority of deaths from cancer are caused by the tumor invasion and metastasis. Epithelial-mesenchymal transition (EMT) is critical for appropriate embryonic development, and this process is re-engaged in adults during wound healing, tissue regeneration, organ fibrosis, and cancer invasion and metastasis. EMT can be prompted by various intrinsic signals (e.g. gene mutations) as well extrinsic signals (e.g. growth factor signaling). Among the growth factors known to induce EMT are transforming growth factor β (TGF-β) and epidermal growth factor (EGF) family. We have used TGF-β and EGF to induce nasopharyngeal carcinoma (NPC) cell to undergo EMT, and profiled the mRNA and miRNA expression pattern changes in this process. We discovered a few of miRNA related feedback and feedforward loops involving in the EMT process. We observed an upregulation of miR-505, and miR-1207-5p upon EMT, and found that all of them could suppress tumor cell migration and invasion abilities, conferring robustness to the EMT process. In this proposal, we will systematically investigate the downstream target genes of miR-505 and miR-1207-5p in the EMT process; evaluate whether their inhibition of EMT depend on their ability to suppress TGF-β and Wnt/β-catenin signaling; explore their roles of controlling the TGF-β-induced "EMT or apoptosis switch" and their roles in the tumor microenvironment. The illumination of the microRNA's role in conferring robustness to EMT process may help us to understand their function in preventing cancer invasion and metastasis, and provide new possibility to discover useful therauptic targets for cancer metastasis.