循环lncRNA POU3F3促进食管鳞癌细胞增殖和侵袭的分子机制

LncRNA dysfunction has been shown to be involved in tumor initiation, invasion, and metastasis by modulating oncogenic and tumor suppressing pathways. In the previous study, we found that plasma levels of lncRNA POU3F3 was significantly higher in esophageal squamous cell carcinoma (ESCC) patients compared with healthy controls, and was associated with lymph node metastasis, treatment response and tumor progression. Inhibition of lncRNA POU3F3 resulted in inhibition of cells proliferation and invasion. Our in vitro assay confirmed that tumor-secreted exosomes can carry and deliver lncRNA POU3F3 to recipient cells, leading to toll like receptors activation and proinflammatory cytokine production. Therefore, we hypothesized that tumor-secreted lncRNAs within exosomes could be transferred from cell to cell and could promote tumor progression by binding to toll like receptors in receiving cells. The aim of the present study was to investigate the expression level of lncRNA POU3F3 in ESCC and its clinical value, to explore the origin and transport mechanism of lncRNA POU3F3 in plasma, to disclose the mechanism of lncRNA POU3F3-induced inflammatory cells activation, and to explore the role of circulating lncRNA POU3F3 in tumor proliferation and invasion. All of this will help us understand the role of circulating lncRNA POU3F3 played in ESCC progression and the pathway involved.

研究发现lncRNA异常表达与肿瘤发生、侵袭及转移密切相关。我们前期研究发现：lncRNA POU3F3在食管鳞癌患者血浆中高表达，并且与淋巴结转移、放化疗疗效及疾病进展相关；敲低lncRNA POU3F3降低食管鳞癌细胞增殖及侵袭能力；外泌体可转运lncRNA POU3F3至受体细胞，使受体细胞增殖及侵袭能力增加；细胞实验证实lncRNA POU3F3存在与TLR7和TLR8结合，激活NF-κB通路可能性。因此我们提出食管鳞癌细胞可通过外泌体转运lncRNA POU3F3至邻近细胞，靶向结合受体细胞内TLR7和TLR8，激活NF-κB信号通路，促进肿瘤进展假说。本项目拟采用多种细胞及动物模型，以及分子生物学实验技术，明确其在食管鳞癌中表达及临床意义，揭示其促进肿瘤细胞增殖侵袭的分子机制。本项目将为食管鳞癌发生发展机制研究开拓新的视野，为食管鳞癌治疗提供新的理论依据和研究方向。

肿瘤细胞可通过外泌体途径，分泌转运lncRNAs至受体细胞，参与调控化疗抵抗。本课题研究发现食管鳞癌细胞可通过外泌体途径分泌lncRNA POU3F3,且证实细胞上清液及血浆中lncRNA POU3F3主要存在于外泌体中。外泌体可转运lncRNA POU3F3至食管鳞癌细胞，促进其增值，侵袭迁移及顺铂耐药。同时食管鳞癌细胞分泌的外泌体可转运lncRNA POU3F3至正常成纤维细胞，诱导其激活成为肿瘤相关成纤维细胞，通过启动NF-κB信号通路，促进炎症介质IL-6释放，促进肿瘤细胞增殖，抑制顺铂诱导的细胞凋亡。我们同时分析了正常人，食管鳞癌患者血浆外泌体中lncRNA POU3F3表达，初步证实其可作为食管鳞癌诊断及放化疗疗效预测的分子标志物。