外泌体miRNAs介导FGFR/GLI2信号通路调控肺鳞癌干细胞表型及侵袭转移的分子机制

Lung squamous cell carcinoma has a high malignancy with rapid progression and poor survival. The stem cells are related with tumor invasion and metastasis. FGFR1 is one of the most common potential druggable driving genes in lung squamous cell carcinoma. Our previous studies suggested that the frequency of FGFR1 amplification was 43% in Chinese lung squamous cell carcinoma patients. FGFR1/GLI2 signaling pathway played an important role in the maintenance of stem cell phenotype in lung squamous carcinoma cells. We also found that the expression of miR-106b was dramatically different between metastatic and non-metastatic squamous carcinoma tissue samples. In lung squamous carcinoma cell lines, FGFR1 can regulate the expression of miR-106b. So miR-106b may play a key molecular role between lung squamous cell carcinoma stem cell self-renewal and invasion, metastasis. This study will further elaborate how miR-106b regulates FGFR1/GLI2 signalling pathway, maintenances of stem cell phenotype in lung squamous carcinoma cells，tumor invasion and metastasis; and the effect of cancer-secreted exosomes miR-106b on endothelial barrier integrity and metastasis in lung squamous cell carcinomas. Applicants will further explore the molecular mechanism that how miR-106b regulates lung squamous cell carcinoma stem cell-like phenotype maintenance, invasion and metastasis. It will be helpful for further lung squamous cell carcinoma target treatment.

肺鳞癌具有恶性程度高、进展快、疗效差等特点，其干细胞参与肿瘤侵袭和转移。FGFR1是肺鳞癌常见潜在可药化驱动基因，我们的研究提示中国肺鳞癌患者FGFR1扩增达到了43%，FGFR1/GLI2信号通路在维持肺鳞癌细胞的干性表型的过程中扮演重要的作用；miR-106b是在转移性和非转移性肺鳞癌组织样本中差异最为显著的miRNA之一，在肺鳞癌细胞系中，FGFR1能调控miR-106b的表达。miR-106b有可能是衔接肺鳞癌干细胞自我更新的维持及肺鳞癌血道转移的关键分子。本研究将深入阐述：miR-106b如何介导FGFR1/GLI2信号通路调控肺鳞癌干细胞表型及肿瘤侵袭转移；外泌体miRNA-106b对血管内皮屏障完整性及肺鳞癌转移的影响。申请者将进一步对肺鳞癌干细胞表型的维持及其侵袭转移的分子机制进行深入探究，并探讨可能的干预靶点，为临床肺鳞癌的靶向治疗提供新的诊疗思路。

肺鳞癌具有恶性程度高、进展快、疗效差等特点。FGFR1是肺鳞癌常见潜在可药化驱动基因，我们的研究发现FGFR1信号通路与其他信号通路之间存在“信号交联”，共同调节肺鳞癌的干性表型、表皮间质转化、肺癌细胞自噬等复杂的生物学行为。FGFR1通过FGFR1-ERK- beclin1信号通路调控NSCLC细胞的细胞自噬过程。FGFR1与Hippo信号通路的交互作用，FGFR1与YAP1相互调节，共同调控肺鳞癌细胞干性表型。FGFR1通过FGFR1-ERK1/2-SOX2信号通路轴驱动FGFR1扩增的非小细胞肺癌细胞EMT转化和侵袭转移。miRNA-214与FGFR1存在相互反馈调控，miRNA-214通过抑制FGFR1抑制下游Wnt/MAPK/PI3K-AKT信号通路，并抑制FGFR1扩增细胞的增殖和侵袭转移和EMT转化。miR-499a-5p在外泌体中的含量显著升高，miRNA-449a通过调控mTOR信号通路促进肺癌细胞增殖迁移和EMT转化。在此基础上继续拓展研究了免疫治疗与肠道菌群之间的关系、新驱动基因的靶向治疗、肿瘤代谢活性与靶向治疗疗效等相关领域，为后续针对肺鳞癌相关分子信号通路的深入研究奠定了基础，为临床靶向治疗提供新的诊疗思路。