靶向炎症信号通路的lncRNA调控乳腺癌细胞可塑性的研究

Noncoding RNAs (ncRNA) participate in multiple cellular processes and modulate tumorigenesis and cancer development by interfering with protein expression and function. Our previous findings demonstrated that microRNAs regulate the plasticity of breast cancer cells and thus determine the fates of tumor initiation, metastasis and therapeutic resistance. Our preliminary data showed that a long noncoding RNA (lncRNA), KBIR1, participates in the negative feedback circuitry of NFκB signaling and modifies the plasticity of breast cancer cells under inflammatory microenvironment. Therefore, our present study aims to examine the differential expression profile of lncRNAs in breast cancer cells induced by inflammatory cytokines and explore their functional roles in tumor cell plasticity and cancer metastasis in vitro and in vivo. Furthermore, we will investigate the mechanism of differential lncRNA expression and their interaction with inflammatory signaling proteins to regulate protein expression, modificatoin and functions. Our study will shed light on the role of lncRNAs participating in inflammation induced tumor cell plasticity and tumor progression, and will help to provide novel molecular targets for therapies against breast cancers.

非编码RNA（ncRNA）通过干预蛋白的表达和功能调节细胞生物学特性，并影响肿瘤发生发展。我们前期研究发现微分子ncRNA（microRNA）参与调控肿瘤细胞可塑性，包括上皮间质转化（EMT）和肿瘤干细胞分化，从而决定肿瘤发生、转移和治疗耐受等。进一步预实验结果显示长非编码RNA（lncRNA）KBIR1参与炎症NFκB信号通路的负反馈调节，影响炎症微环境诱导的肿瘤细胞可塑性变化。在前期我们筛选的炎症因子诱导差异表达的lncRNA基础上，本课题拟通过干预表达，在体外和体内模型中探索lncRNA对乳腺癌细胞可塑性与肿瘤转移的调控功能。并进一步阐述lncRNA在炎症因子作用下差异表达的机制，及其与炎症信号蛋白相互作用的分子机理和调节蛋白表达、修饰和功能发挥的作用。研究将有助于揭示lnRNA参与炎症微环境调控肿瘤细胞可塑性及肿瘤发展的分子机制，并为靶向lncRNA治疗肿瘤的策略提供新的分子靶点。

非编码RNA（ncRNA）通过干预蛋白的表达和功能调节细胞生物学特性，并影响肿瘤发生发展。我们预实验结果显示长非编码RNA（lncRNA）NKILA参与炎症NFκB信号通路的负反馈调节，影响炎症微环境诱导的肿瘤细胞可塑性变化。本课题研究工作在已建立的炎症微环境与肿瘤细胞相互作用模型、炎症细胞体外共培养模型及人源化荷瘤小鼠体内模型基础上，发现并鉴定了肿瘤间质炎症微环境与肿瘤细胞相互作用导致肿瘤发生和进展的关键细胞因子，并通过lncRNA微阵列芯片检测建立了多种炎症因子诱导乳腺癌细胞EMT和肿瘤干细胞表型变化过程中lncRNA的表达谱，通过干预表达，在体外和体内模型中探索lncRNA对乳腺癌细胞可塑性与肿瘤转移的调控功能。并进一步阐述lncRNA在炎症因子作用下差异表达的机制，及其与炎症信号蛋白相互作用的分子机理和调节蛋白表达、修饰和功能发挥的作用。研究将有助于揭示lnRNA参与炎症微环境调控肿瘤细胞可塑性及肿瘤发展的分子机制，并为靶向lncRNA治疗肿瘤的策略提供新的分子靶点。