转移性肺癌当中排斥性导向分子RGMs的功能和机制研究及其与BMP信号通路的关联

Bone is a frequent target of lung cancer metastasis, and is associated with significant morbidity and a dismal prognosis. Repulsive guidance molecules (RGMs) are novel co-receptors of bone morphogenetic proteins (BMPs) which have been implicated in bone metastasis of cancer. RGMs were shown to play vital inhibitory roles in breast cancer and prostate cancer in my previous studies, altered tumour cell biological behaviours including proliferation, adhesion, migration and motility through BMP signalling. This study was aimed to investigate key roles of RGMs played in lung cancer and bone metastasis. .We are aimed to learn the expression profile of RGMs in cell lines and a panel of clinical cohort of lung cancer. The expression of RGMs in lung cancer will be associated with clinical prognosis. The effects of RGMs in lung cancer will be fully investigated in vitro and in vivo through cell function assays and establishment of nude mice models, following gene knockdown and overexpression studies. The mechanisms underlying these effects and signal pathways will be more interesting and important..This study will firstly reveal the novel roles of RGMs in lung cancer which might be a key factor in cancer progression and metastasis. RGMs might be a new predictor of prognosis and potential target of gene therapy for lung cancer.

肺癌是全球范围内高致死率的恶性肿瘤之一，影响其预后的关键因素是肺癌的转移。排斥性导向分子RGMs可改变恶性肿瘤细胞生物学行为，具有抑制其侵袭和转移的能力，是抑制肿瘤转移的重要候选靶基因。RGMs是骨形态发生蛋白BMPs的合作受体，已有研究表明BMPs与肺癌转移有关，在肺癌发生和转移过程中起关键作用。前期研究证实，RGMs在肺癌组织中的表达明显下调，那么，RGMs在肺癌发生与转移中作用如何？或是否与BMPs共同参与了肺癌转移的调控？都是值得探讨的重要问题。因此，本课题试图分析肺癌中RGMs的表达状况及其与肺癌转移和临床预后的相关性；然后利用核酶敲除技术分别研究RGMs对肺癌细胞株侵袭和转移特性的影响；最后分析RGM对BMP-Smad 信号通路的相互作用。初步探讨RGMs在肺癌转移中的作用机制，为临床应用RGMs作为候选靶点治疗肺癌转移奠定基础。

肺癌转移是一个极其复杂的多基因调控和多阶段、多步骤发生的过程。本项研究目的旨在阐明排斥性导向分子和骨形态发生蛋白途径相关分子的内在联系和分子调控机理，以及肺癌侵袭转移的信号传导调节途径，从而揭示肺癌侵袭转移的分子机理，阐明排斥性导向分子在肺癌侵袭转移过程中的作用和调控网络，并为开发以肺癌侵袭转移相关基因为靶点的基因治疗和分子靶向药物提供理论基础和实验依据。主要成果：检测了肺癌转移相关基因RGMB等在肺癌中的表达情况并分析其预后的相关性；通过RNA干扰基因敲减等技术建立基因变异细胞株；为了研究其分子机理，成功合作开发了肺癌小鼠pdx模型，完成了不同肺癌细胞株侵袭转移表型差异的体内外研究，并进一步检测了其抑制癌症转移所作用的调控通路。