ETS1/LIF信号介导癌相关成纤维细胞促进乳腺癌进展的功能与机制研究

Breast cancer is now the most common malignant tumor in women. The mechanisms underlying breast cancer progression have not been fully elucidated. Cancer microenvironment, especially cancer associated fibroblasts(CAFs), has been proved to be essential for cancer progression. However, the role of CAFs in breast cancer progression has not been well defined. Our primary experiments demonstrate that CAFs can promote the growth, migration and invasion of breast cancer. The high-throughput sequencing data display that ETS1 is highly expressed and involved in the transcriptional regulation of nearly half of significantly upregulated genes in CAFs. Knockdown of ETS1 in CAFs attenuates the pro-invasive and pro-migratory effects of CAFs on breast cancer cells. Moreover, HTRI data analyses and the results that knockdown of ETS1 in CAFs leads to decreased leukemia inhibitory factor(LIF) mRNA levels, indicate that LIF is probably the downstream target of ETS1 in CAFs. Thus, we propose the hypothesis that highly expressed ETS1 in CAFs increases the production and secretion of LIF, which promotes the progression of breast cancer. Based on in vitro and in vivo experiments, our project aims to elucidate the function of CAFs during the progression of breast cancer, to explore the role of ETS1 in CAFs and further study the mechanisms of ETS1/LIF signaling in CAFs, which will provide a new theoretical basis for the treatment of breast cancer.

乳腺癌是女性最常见的恶性肿瘤，调控其进展的机制还未完全阐明。癌间质微环境，尤其是癌相关成纤维细胞(CAFs)，在癌症进展中发挥关键的作用，而CAFs在乳腺癌进展中的功能和机制还未详细阐述。我们的研究结果表明CAFs促进乳腺癌的生长迁移和侵袭，高通量测序分析显示转录因子ETS1在CAFs中高表达并参与了近半数显著上调基因的转录调控。CAFs中敲低ETS1可抑制其促乳腺癌迁移和侵袭能力。HTRI数据与预实验显示CAFs中敲低ETS1抑制了白血病抑制因子(LIF)的转录，提示LIF可能是ETS1下游靶点。因此，我们提出科学假设：乳腺癌CAFs中ETS1高表达，导致LIF合成和分泌增加，从而促进乳腺癌进展。本项目拟从细胞和动物两层面阐释CAFs在乳腺癌进展中的功能，探究ETS1在乳腺癌CAFs中的作用，并深入研究CAFs中ETS1/LIF信号促乳腺癌进展的机制，为乳腺癌的治疗提供新的理论依据。

乳腺癌是女性最常见的恶性肿瘤，癌间质微环境在癌症进展中发挥了重要的作用。作为癌间质微环境中含量非常丰富的一种细胞，癌相关成纤维细胞(CAFs)在乳腺癌进展中的功能及机制尚不清楚。我们的研究结果发现CAFs促进了乳腺癌的生长迁移和侵袭。高通量测序分析结果显示CAFs与正常成纤维细胞NFs的基因表达谱有明显的差异，转录因子ETS1在CAFs中高表达并可能参与大量显著上调基因的转录调控。功能实验显示敲低ETS1抑制了CAFs促乳腺癌细胞迁移及侵袭的功能，过表达ETS1则增强了NFs促乳腺癌细胞迁移及侵袭的功能。并且我们还发现白血病抑制因子(LIF)是ETS1的下游靶点，揭示了ETS1/LIF信号促乳腺癌进展的机制，为乳腺癌的治疗提供了新的理论依据。本项目经费资助下共发表2篇SCI论文。