基于IL-6/STAT3/miR-196a轴介导的拟黑多刺蚁活性组分抑制乳腺癌发生发展的机制研究

Breast cancer (BC) is a major contributor of cancer-associated mortality in women. It is crucially important to research and develop new breast cancer inhibition agents with high efficiency. Polyrhachis vicina Roger，a traditional Chinese medicine，are quite rich in Guangxi. It’s proved to possess good anti-tumor activity and has wide prospect of application, but the molecular mechanisms of anti-tumor effect is still unclear. Our preliminary study demonstrated that the active fraction from Polyrhachis vicina Roger (AFPR) could inhibit the proliferation and migration of BC cells; IL-6 and miR-196a were down-regulated in the MCF7 cells treated with AFPR. We further found that miR-196a may be regulated by IL-6/STAT3 signaling in BC. We therefore speculated that AFPR inhibit breast cancer progression via the IL-6/STAT3/miR-196a axis. In this project, we will further determine the inhibition of AFPR in breast malignant progression, and explore wether the IL-6/STAT3/miR-196a axis play an important role in this process. This study will lay the foundation for developing Polyrhachis vicina Roger as anti-tumor agents, and provide novel thoughts for studies on anti-tumor mechanism of traditional Chinese medicine.

乳腺癌是女性最常见的恶性肿瘤之一，发病率逐年增高，严重威胁广大女性健康。因此，研发新的高效抗乳腺癌药物迫在眉睫。拟黑多刺蚁为广西道地药材，具有良好的抗肿瘤活性，应用前景广阔，但其作用机制尚不明确。我们前期发现拟黑多刺蚁活性组分(AFPR)能抑制乳腺癌细胞的增殖和迁移，IL-6和miR-196a在给予AFPR处理的乳腺癌细胞中表达下调，且IL-6可能通过STAT3调控miR-196a的表达。因此我们推测：AFPR可能通过抑制IL-6/STAT3/miR-196a轴发挥其抗乳腺癌作用。本项目拟在前期基础上进一步明确AFPR对乳腺癌恶性进程的抑制作用，并探究IL-6/STAT3/miR-196a/相关靶基因在AFPR抑制乳腺癌发生发展中的作用机制，为开发拟黑多刺蚁作为治疗乳腺癌药物奠定基础，为中药抗肿瘤作用机制研究提供新思路。

乳腺癌是女性最常见的恶性肿瘤之一，其发病率逐年增高，严重危害广大女性的健康。本项目通过细胞增殖实验，细胞划痕实验，侵袭实验和裸鼠成瘤实验来检测拟黑多刺蚁活性组分（AFPR）对乳腺癌的影响。进行基因芯片测序，qRT-PCR，Western blot，染色质免疫共沉淀和荧光素酶报告基因实验，研究AFPR对相关基因的调控及其潜在机制。结果表明，AFPR在在体外抑制了乳腺癌细胞的生长，迁移和侵袭，在体内抑制了乳腺癌肿瘤的生长。研究发现，AFPR对炎症因子IL-6、IL-1β 和TNF-α，炎症信号通路NF-κB的具有显著的抑制作用，明确了AFPR在乳腺癌中对炎症的抑制作用。研究进一步发现，AFPR对非编码RNA（lncRNA、miRNA）具有调控作用，能下调miR-196a表达。在乳腺癌中miR-196a靶向SPRED1，抑制乳腺癌的生长，而AFPR可以下调miR-196a的表达和上调SPRED1的表达。在经AFPR处理的MCF7细胞中，LncRNA NKILA显著上调。AFPR通过调节NKILA使NF-κB信号通路失活和促炎因子的释放减少。研究表明AFPR通过miR-196a/SPRED1和EGR1/NKILA/NF-κB轴抑制乳腺癌的恶性进程。..本项目的研究内容已全部完成，本研究为开发拟黑多刺蚁成为药物奠定基础，为研制具有自主知识产权的抗乳腺癌药物奠定基础。在本项目的资助下，共发表论文4篇，其中SCI论文2篇，中文核心学术期刊论文2篇；申请国家发明专利1项，获得国家发明专利授权1项。