环状RNA介导肿瘤相关巨噬细胞促进肺癌转移研究

Circular RNA plays a key role in the development of malignant tumors, but its mechanism of promoting tumor invasion and metastasis in tumor microenvironment has not been reported yet. Our previous experimental results suggest that the circular RNA circ0005654 is highly expressed in lung cancer with metastasis and is associated with poor prognosis. Meanwhile, circ0005654, up-regulated expressed in lung cancer cells, can promote differentiation of M0-type macrophages to Tumor-associated macrophages in the tumor microenvironment. Tumor-associated macrophages activated by circular RNA can further secrete inflammatory factors up-regulated circ0005654 expression and promote lung cancer invasion and metastasis, thus forming a malignant loop. On this basis, we will further elucidate the molecular mechanism by which circ0005654 mediates the interaction between lung cancer cells and tumor-associated macrophages to promote lung cancer metastasis, and reveal the molecular mechanisms by which circular RNA participates in regulating the biological characteristics of tumor cells in inflammatory microenvironment, and provide a theoretical basis for the treatment of lung cancer metastasis by targeting circular RNA.

环状RNA在恶性肿瘤的发生发展中起到关键作用，但其在肿瘤微环境中促进肿瘤侵袭转移的作用机制仍未见报道。我们预实验结果提示，环状RNA circ0005654在肺癌伴转移的组织中异常高表达并与不良预后相关，与此同时，肺癌细胞表达上调的circ0005654在肿瘤炎症微环境中可促进M0型巨噬细胞向肿瘤相关巨噬细胞极化，受环状RNA介导激活的肿瘤相关巨噬细胞又可进一步分泌炎症因子上调circ0005654表达促进肺癌侵袭转移，从而形成恶性环路。在此基础上，本课题将进一步阐明circ0005654介导肺癌细胞和肿瘤相关巨噬细胞互作调控从而促进肺癌转移的分子机理，揭示环状RNA参与炎症微环境调控肿瘤细胞生物学特性的分子机制，并为靶向环状RNA治疗肺癌转移提供理论依据。

环状RNA在恶性肿瘤的发生发展中起到关键作用，但其在肿瘤微环境中促进肿瘤侵袭转移的作用机制仍未见报道。我们实验结果提示，环状RNAcirc0005654在肺癌伴转移的组织中异常高表达并与不良预后相关，与此同时，肺癌细胞表达上调的circ0005654在肿瘤炎症微环境中可促进M0型巨噬细胞向肿瘤相关巨噬细胞极化，受环状RNA介导激活的肿瘤相关巨噬细胞又可进一步分泌炎症因子上调circ0005654表达促进肺癌侵袭转移，从而形成恶性环路。机制上circ0005654 通过海绵 miR-491-5P， 从而影响上调 NOTCH3 的表达， 导致NOTCH3 通路的激活， 进一步导致了肿瘤细胞的侵袭迁移增加，同时在临床标本中验证了circ0005654的上调会导致病人的不良预后，同时体外动物实验验证了circ0005654的过表达促进了肿瘤的进展，本项研究结果揭示环状RNA参与炎症微环境调控肿瘤细胞生物学特性的分子机制，并为靶向环状RNA治疗肺癌转移提供理论依据。