miR-1207-5p通过Wnt/β-catenin信号通路调节肿瘤干细胞活性影响转移前龛形成的机制研究

Pre-metastatic niche is a favorable microenvironment for subsequent metastases and invasion of cancer cells in secondary organs and tissue sites and is mainly established through a complex interaction of factors that derived from primary tumor, including exosomes. It has been reported that the cancer stem cell (CSC)-derived exosomes could promote pre-metastatic niche formation and the microRNAs in exosomes might play a key role in the regulation. Our previous studies confirmed that the miR-1207-5p could regulate the CSC behavior by inhibiting β-catenin expression and had significant effect on angiogenesis and the functions of tumor-associated macrophages in tumor microenvironment. However, the underlying mechanisms are still unclear. In this project, we propose to identify the roles of miR-1207-5p in pre-metastatic niche formation from two aspects. i) To reveal the mechanism of miR-1207-5p in regulating β-catenin expression through non-coding RNA interaction and post-translational modification. ii) To detect the effect of miR1207-5p on CSC transcriptome and the constituent of exosomes through high-throughput sequencing, mass spectrometry and animal models. Our findings would provide a potential target for prevention and treatment of cancer metastasis and invasion.

转移前龛是肿瘤转移的重要条件，主要由原发部位的肿瘤细胞通过外泌体等多种形式对靶器官微环境进行“改造”而形成。目前已有报道肿瘤干细胞来源的外泌体可以促进转移前龛的形成，microRNA作为外泌体的成分之一，在这一过程中发挥重要作用。我们前期研究发现，miR-1207-5p可以下调β-catenin蛋白水平调控肿瘤干细胞活性，影响肿瘤微环境中的血管生成和肿瘤相关巨噬细胞的功能，抑制肿瘤转移和生长，但其分子机制还未明确。本项目将从非编码RNA和蛋白质修饰方面研究miR-1207-5p对β-catenin的分子调控机制，通过动物模型、高通量测序和质谱分析研究miR-1207-5p对肿瘤干细胞转录组及其外泌体成分的影响，深入解析miR-1207-5p对转移前龛的调控作用。我们的研究成果将为肿瘤转移的防治提供新的靶点。

鼻咽癌是常见的头颈部肿瘤，在中国南方地区高发。调查显示，30%的鼻咽癌患者会出现复发，30%-60%的患者会出现转移。但目前关于鼻咽癌侵袭转移和复发的分子机制尚未明了。大量证据表明，Wnt/β-catenin信号通路在鼻咽癌中高度活化，维持了肿瘤干细胞的活性，导致了肿瘤耐药复发和侵袭转移。而近年来研究表明，microRNA的表达失调是鼻咽癌等肿瘤发生发展的因素之一。.本项目前期研究已发现miR-1207-5p可能是一个新的肿瘤抑制因子，对Wnt/β-catenin信号通路具有调节作用，从而负调控鼻咽癌的生长和侵袭转移。本项目在前期基础上进一步通过细胞模型、动物模型明确了miR-1207-5p可以靶向抑制PDK1的表达，并通过PDK1/AKT/β-catenin信号途径抑制β-catenin入核，抑制Wnt/β-catenin信号通路的活化，从而调节肿瘤干细胞活性，抑制肿瘤干细胞的自我更新和增殖生长。同时，本研究还发现了miR-1207-5p能够通过外泌体调控肿瘤转移前龛，抑制巨噬细胞向M2型分化，从而抑制肿瘤转移。.本项目的研究结果进一步表明，miR-1207-5p是一个新的肿瘤抑制分子，可以通过抑制Wnt/β-catenin信号通路调控肿瘤干细胞活性，并通过调控肿瘤相关巨噬细胞的招募，影响肿瘤转移前龛的形成，是肿瘤发生发展的重要调控分子，为肿瘤的防治和靶向治疗提供了新的理论依据。