FOXM1-lncRNA通路调控上皮间质转化和肿瘤干细胞参与肺腺癌转移的机制研究

The epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) play a critical role during the process of invasion and metastasis in lung adenocarcinoma. EMT could promote the acquisition of stem-like properties in cancer cells and CSC has EMT properties, however, the underlying mechanism of the interaction between EMT and CSC still remains unclear. We previously found FoxM1 transcriptional regulated Snail which is critical for EMT mediated metastasis of lung adenocarcinoma. FoxM1 could maintain the stem cell property. Long noncoding RNAs (lncRNA) is a group of RNAs, which is longer than 200 nucleotides and can not encode proteins. We found FoxM1 could transcriptional regulate a group of lncRNAs, which is crucial for EMT and CSC for metastasis of lung adenocarcinoma. Here, we proposed for the first time that FoxM1 might serve as a key modulator of signalling cross talk between EMT and CSC, which is responsible for the metastasis of lung adenocarcinoma, possibly through transcriptional regulated a group of lncRNAs. In this study, we aim to elucidate the mechanism of FoxM1 involved in lung adenocarcinoma metastasis through transactivation of lung CSC with EMT property, which is helpful to identify critical marker and therapeutic target.

肿瘤转移与上皮间质转化（EMT）和肿瘤干细胞(CSC)密切相关。EMT可促进肿瘤细胞获得CSC干性，而CSC具有EMT样特征，两者相互作用机制尚不清楚。我们前期发现转录因子FoxM1介导Snail参与EMT相关的肺腺癌转移；FoxM1可维持肺腺癌CSC干性，推测FoxM1可能是肺腺癌EMT与CSC信号串话的关键节点之一。长链非编码RNA（lncRNA）是一组长度大于200 nt、不编码蛋白质的RNA分子，我们发现FoxM1可能在转录水平调控一组lncRNA，该组lncRNA可能通过调控EMT和CSC进而参与肺腺癌转移过程。据此我们首次提出FoxM1通过调控下游lncRNA参与肺腺癌EMT和CSC的内在转化，进而促进肺腺癌转移。本课题拟通过体内外实验，初步阐明FoxM1-lncRNA通路介导EMT样肺腺癌CSC形成和干性维持，进而参与肺腺癌转移的的机制，最终为肺腺癌的诊疗提供新的候选靶点。

肺癌是世界范围内发病率和死亡率最高的恶性肿瘤，尽管以吉非替尼为代表的生物靶向治疗等综合治疗手段部分提高了肺腺癌疗效，但远处转移仍然是制约肺腺癌病人长期生存的主要原因。因此探寻肺腺癌转移的关键基因及其生物学机制，对肺腺癌的治疗及预后评估具有重要的临床转化应用价值。本课题组发现转录因子FoxM1参与EMT相关的肺腺癌转移，通过RNA-Seq技术筛选出FoxM1可能在转录水平调控的一组lncRNA，通过Real-time PCR在肺腺癌细胞系中以及69组肺腺癌病人癌和癌旁组织的验证，本项目组发现lncRNA IQCJ-SCHIP-AS1与FoxM1的表达正相关，并且在肺腺癌病人癌组织中显著高表达。在进一步的功能研究中发现，IQCJ-SCHIP-AS1参与了肺腺癌细胞系的EMT进程，参与了肺腺癌细胞系的侵袭迁移。本课题通过体内外试验将阐明FoxM1- IQCJ-SCHIP-AS1通路介导肺腺癌EMT进程，进而参与肺腺癌转移的机制，最终为肺腺癌的诊疗提供新的候选靶点。.