HOTAIR介导CAFs促进乳腺癌紫杉醇耐药和转移的作用机制及靶向治疗

The interaction of carcinoma-associated fibroblasts (CAFs) and tumor cells is the major cause of breast cancer metastasis and drug resistance. We previously found that LncRNA HOTAIR was overexpressed in various solid tumors and CAFs can significantly promote the expression of HOTAIR, paclitaxel resistance and metastasis of breast cancer cells. These suggest that HOTAIR may play an important role in the mediation of CAFs-induced paclitaxel resistance and metastasis of breast cancer cells. In this proposal, we will focus on study the role and molecular mechanisms of HOTAIR in mediation of CAFs-induced breast cancer metastasis and chemotherapy resistance: We will test our hypothesis “CAFs-secreted cytokines may promote the HOTAIR expression and the increasing expression of HOTAIR may further modulate the histone modification and activate both NF-κB/β-catenin and EGR-1/CDK5 signal pathways, and then consequently initiating the chemotherapy resistance and tumor metastasis”; Moreover, we will design and optimize the functional Au nanoparticles to carry both HOTAIR antisense nucleic acids and paclitaxel, to achieve effective dual-drug delivery for targeted cancer therapy. In summary, this research proposal will reveal the new mechanism of HOTAIR-mediated chemotherapy resistance and tumor metastasis in the tumor microenvironment and may lead to a new tumor-targeted drug delivery strategy.

肿瘤相关成纤维细胞（CAFs）与肿瘤细胞的相互作用是诱导乳腺癌细胞转移和化疗耐药的重要原因；我们发现，LncRNA HOTAIR在多种实体瘤中异常表达，且CAFs可明显促进肿瘤细胞中HOTAIR高表达。据此，本项目拟对CAFs与乳腺癌细胞相互作用后HOTAIR如何参与调控乳腺癌细胞化疗耐药及转移开展研究:首先,采用细胞因子阵列分析等技术检测CAFs分泌的细胞因子,确定CAFs诱导乳腺癌高表达HOTAIR和紫杉醇耐药的交叉细胞因子；其次，研究HOTAIR介导CAFs诱导的乳腺癌细胞化疗耐药及转移的分子机制,推测与HOTAIR调控组蛋白修饰,进而激活NF-κB/EGR双重信号通路有关。最后，构建表面功能化的金纳米微粒，同载HOTAIR反义核酸与化疗药物，实现联合药物的靶向投递。本研究将揭示CAFs促进乳腺癌化疗耐药和转移过程中LncRNA的新作用机制，并为研发新一代肿瘤靶向治疗药物奠定基础。

肿瘤相关成纤维细胞（CAFs）与肿瘤细胞的相互作用是诱导乳腺癌转移的重要原因。我们发现，LncRNA HOTAIR在多种实体瘤中异常表达，且CAFs可明显促进肿瘤细胞中HOTAIR高表达。据此，本项目拟对CAFs与乳腺癌细胞相互作用后HOTAIR如何参与调控乳腺癌细胞转移及其靶向治疗开展研究。. 本课题组发现，乳腺癌中CAFs通过分泌细胞因子TGF-β1激活肿瘤细胞内SMAD2/3信号通路，进而转录激活HOTAIR促进乳腺癌细胞的转移活性，阐明了CAF促进乳腺癌转移的分子机制，证实HOTAIR可以作为乳腺癌治疗的靶点。本课题以肿瘤微环境与肿瘤细胞的相互作用为基础，从肿瘤微环境介导的 LncRNA 及信号通路的异常表达出发，从肿瘤微环境及表观遗传学角度入手解析肿瘤转移的新型分子机制。相关研究成果以通讯作者发表在Molecular cancer杂志。. 此外，基于HOTAIR的结构和功能，以HOTAIR 5’端-EZH2相互作用的212-300nt序列为作为靶点，以NCI Diversity Set数据库中具有成药潜能的近2000种化合物作为候选筛选对象，利用AutoGrid4和AutoDock4软件进行分子对接，筛选并确定AC1NOD4Q 为HOTAIR的小分子抑制剂。AC1NOD4Q通过靶向Wnt/β-catenin信号通路抑制肿瘤侵袭和转移，为以核酸为靶标的肿瘤治疗开辟了新的方向，为研发新一代肿瘤靶向治疗药物奠定基础，具有重要的转化医学意义。相关研究成果以通讯作者发表在Clinical Epigenetics杂志。. 在国家自然科学基金委员会面上项目的资助支持下，本课题组在Molecular Cancer, Clinical Epigenetics、Cancer Letters等高水平期刊共发表SCI文章5篇，累计影响因子超过30，其中单篇最高影响因子15.302。本项目顺利完成了预定的全部研究任务，达到了预期的效果。