STMN1通过调控p38MAPK/STAT1信号通路介导肺腺癌转移的作用及机制研究

Metastasis is the leading cause of death in patients with lung adenocarcinoma, which has no available treatment. Our previous study found that over-expression of STMN1 in lung adenocarcinoma tissue showed to be closely correlated with the activation of p38 MAPK and STAT1, as well as lymphatic metastasis; activation of p38 MAPK and STAT1 can be inhibited by down-regulating STMN1 expression, metastatic potential be decreased significantly also. Therefore, we hypothesize that "STMN1 may promote EMT through p38 MAPK/STAT1 pathway in lung adenocarcinoma". Firstly, STMN1 will be overexpressed or knockouted by gene transfection or CRISPR/Cas9 in lung adenocarcinoma cell lines, which would be used to explore its function in modulating p38 MAPK/STAT1 pathway and EMT formation. Secondly, the mechanism, STMN1 controlling p38 MAPK/STAT1 pathway to regulate EMT via modulation of MT stability, will be explicited by using site-specific mutagenesis, RNAi, fluorescence resonance energy transfer. Thirdly, the effect and mechanism of STMN1 modulating EMT via p38 MAPK/STAT1 pathway will be valided by means of IHC and so on. Our research will not only provid new evidences for the treatment of advanced lung adenocarcinoma, but also have wide application prospects.

转移是肺腺癌患者死亡的主要原因，但迄今尚无有效的治疗方法。我们前期发现肺腺癌组织中STMN1表达与p38 MAPK及STAT1活化、肺腺癌淋巴转移密切相关；下调其表达可抑制p38 MAPK及STAT1活化并抑制肺腺癌转移。故提出“STMN1通过调控p38 MAPK/STAT1信号通路促进肺腺癌EMT发生”的假设。本课题应用基因转染和CRISPR/Cas9技术构建STMN1上调及敲除细胞模型，研究STMN1在调节p38 MAPK/STAT1通路活化及肺腺癌EMT中的作用；应用定点突变、RNAi、荧光能量共振转移等方法明确STMN1通过p38 MAPK/STAT1通路调控微管稳定性介导肺腺癌EMT发生的机制；应用免疫组化等方法在裸鼠模型及临床标本中验证STMN1通过p38 MAPK/STAT1通路介导肺腺癌EMT发生的作用及其机制。该研究将为靶向治疗肺腺癌转移提供新的依据，具有广阔的应用前景。