肿瘤相关巨噬细胞通过TGF-β/SOX9信号通路促进肺癌细胞发生EMT

Invasion and metastasis are the most important biological characteristics of lung cancer which are the main clinical cause of death of lung cancer patients. Epithelial-mesenchymal transitons (EMT) is a multi-stage and important process in metastasis. TGF-β is a inflammatory cytokine and its up- regulation is closely associated with various cancers including lung tumors. In this context, TGF-β overexpression by macrophage that was co-cultured with lung cancer cells, and EMT are frequently observed in lung caner cells.However, their functional relationship remains largely unknown. Recent studies have shown that elevated TGF-β levels have been associated with increased SOX 9activation. However, how TGF-βmay contribute to the regulation of SOX9 in EMT has not been fully explored. In this project, we will perform TGF-β neutralization and use siRNA to knockdown the SOX9 expression in vitro , in vivo model and clinical samples. Our study will provide mechanistic insights into howTGF-β regulate the SOX9 in EMT, and the regulation we describe here may have profound therapeutic implications for lung cancer metastasis and angiogenesis and could help invent novel approaches in treating and prognosticating lung cancer. Provide new clues to clarify lung cancer metastasis-related biological mechanisms, and highly metastatic lung cancer for the study of new cytokine-based drug target.

肺癌最重要的生物学特性是侵袭和转移，也是肺癌患者的主要临床致死原因。肿瘤细胞的上皮-间质转化(epithelial-mesenchymal transitons, EMT)是肿瘤发生侵袭、转移的重要原因。我们前期研究发现在肿瘤微环境中巨噬细胞（Mф）向M2型转化，并且高表达TGF-β，使肺癌细胞发生了EMT现象。最新研究发现SOX9过表达促进肿瘤细胞发生EMT，但具体机制不清。利用LASAGNA分析发现TGF-β下游因子Smad3与SOX9的启动子结合位点。本课题将利用已建立体内外模型及临床样本，利用CHIP和荧光素酶报告基因技术确定Smad3与SOX9启动子结合位点，从而阐明TGF-β调控-SOX9表达的分子机制。通过中和Mф分泌的TGF-β，抑制肺癌细胞的SOX9表达，探讨M2型Mф能否过表达TGF-β，进而激活肺癌细胞的SOX9信号通路发生EMT。为临床肺癌治疗提供新的靶点。

肺癌最重要的生物学特性是侵袭和转移，也是肺癌患者的主要临床致死原因，肿瘤细胞的上皮间质转化（epithelia-mesenchymal transition，EMT）是肿瘤发生侵袭、转移的重要原因。我们前期研究发现在肿瘤微环境中巨噬细胞（MΦ）向M2型转化，并且高表达TGF-β，是肺癌细胞发生EMT现象。最新研究表明SOX9过表达促进肿瘤细胞发生EMT,但具体机制不清，我们利用LASAGNA分析发现TGF-β下游因子Smad3与sox9启动子结合位点。我们通过临床样本发现MΦ的数量与SOX9的表达正相关，且高表达预示着预后差。我们建立了体内外模型，证明了MΦ可以促进非小细胞肺癌分泌TGF-β，TGF-β通过C-jun/SAMD3信号通路促进SOX9的表达，从而促进非小细胞肺癌转移。本研究阐明了TGF-β/SOX9在非小细胞肺癌转移的重要作用，明确了TGF-β调控SOX9的具体信号通路，可能为临床治疗肺癌提供有效靶点。