SERPINE2促进食管鳞癌侵袭和转移机制研究

Invasion and metastasis is one of the most important features of malignant tumor development, and is also a major reason for the failure of clinical treatment. In order to study the mechanism of invasion and metastasis of esophageal cancer, we established five esophageal cancer cell subsets with different lung metastasis ability, analysed respectively by RNA-sequence and verified by functional experiments, and found that SRPINE2 could promote invasion and metastasis in esophageal squamous cell carcinoma. However, the mechanism of SERPINE2 promoting tumor invasion and metastasis is not clear. The aim of this study is to clarify the molecular mechanisms of SERPINE2 promoting invasion and metastasis in esophageal cancer cells. Our preliminary data had showed that SRPINE2 could regulate the BMP4/Smads signaling pathway via the transcriptome analysis of its downstream genes and their protein level verification. In the future, We will use multiple models of invasion and metastasis in vitro and in vivo to simulate the invasion and metastasis process of esophageal cancer cell, and analyze the role of SERPINE2/BMP4/Smads signaling pathway at various stages of tumor metastasis and their specific mechanisms. Our subject will provide a theoretical basis for finding new therapeutic targets for esophageal cancer, and offer one novel idea for clinical treatment through studying on the treatment of iExosome targeting SERPINE2 gene.

侵袭转移是恶性肿瘤发生发展的重要特征之一，也是临床治疗失败的重要原因。为了研究食管癌的侵袭转移机制，我们前期建立了具有不同肺转移能力的食管癌细胞亚群，分别对其进行转录组学分析和功能学验证，发现SERPINE2可以促进食管癌侵袭和转移。然而，SERPINE2促进肿瘤侵袭和转移的机制并不清楚。本课题主要目的是阐明SERPINE2促进食管癌侵袭转移的具体分子机制。前期对SERPINE2下游的差异基因进行转录组学分析和蛋白水平验证，发现SERPINE2可以调节BMP4/Smads信号通路。我们将运用多种体内外侵袭转移模型模拟食管癌侵袭转移过程，分析肿瘤转移各阶段SERPINE2/BMP4/Smads信号通路发挥的作用及具体机制，为寻找食管癌新的治疗靶点提供理论依据。并通过构建以SERPINE2基因为靶向iExosome的治疗方法研究，为食管癌的临床治疗提供新的思路。

侵袭转移是恶性肿瘤发生发展的重要特征之一，也是临床治疗失败的重要原因。我们前期建立了具有不同肺转移能力的食管癌细胞亚群，分别对其进行转录组学分析和功能验证，发现SERPINE2可以促进食管癌侵袭和转移。本课题拟研究SERPINE2在食管癌侵袭转移中的作用及其分子机制。我们采用了体内外侵袭迁移实验检测SERPIENE2对食管癌侵袭迁移的影响，运用WB和IHC方法检测SERPINE2对食管癌细胞E-cadherin、N-cadherin和Vimentin等EMT相关基因表达的影响，RNA-seq筛选SERPINE2促侵袭的下游差异基因，qRT-PCR、WB和IHC等多种方法检测SERPINE2通过激活β-catenin/BMP4/Smads信号通路在食管癌侵袭转移中发挥的作用和机制，收集食管鳞癌标本161例，分析SERPINE2与食管癌临床病理参数的相关性。本课题研究结果显示，SERPINE2在食管癌转移中具有重要的作用。SERPINE2与食管癌的临床分期、局部浸润、淋巴结转移密切相关。SERPINE2通过下调E-cadherin，上调N-cadherin、Vimentin、Snail、Slug等EMT相关基因的表达，诱导EMT转化，在促进食管癌细胞肺转移和淋巴结转移方面具有重要的作用。SERPINE2通过激活β-catenin/BMP4/Smads信号通路在食管癌侵袭转移中发挥重要的作用，β-catenin特异性转录抑制剂iCRT14和BMP小分子抑制剂LDN193189均能够有效的抑制SERPINE2诱导的侵袭迁移。本研究阐明了SERPINE2/BMP4/Smads信号通路在食管癌侵袭转移中的作用，并为食管癌的靶向治疗提供了科学依据。