长链非编码RNANR_026829调控S100A9介导肺腺癌脊柱转移的作用及机制研究

Malignant tumor is prone to spinal metastases (SM), especially occurred in adenocarcinoma, which accounts for about 50%. But the mechanism for this phenomenon is not clear. LncRNA regulates gene expression at multiple levels, however, there is not report about whether it involves in SM or not remains unclear. In our preliminary work, high-throughput microarray analysis showed that lncRNANR_026829 was more expressed in SM than that in primary tumors. NR_026829 was closed to gene of S100A9 and NR_026829 silencing could inhibite the expression of S100A9. So S100A9 maybe the target of NR_026829. Immunohistochemistry showed that S100A9 was highly expressed in metastatic neoplasm. The results of preliminary work suggest that NR_026829 may regulate S100A9 to mediate spinal metastasis in lung adenocarcinoma. Therefore immunosuppressive cell (MDSC) and circulating tumor cell (CTC) are selected for this study to explore the mechanism for NR_026829 regulating S100A9 to effect on CTC and MDSC about formation of immunosuppressive microenvironment by molecular biology and immunology methods, such as transcriptional regulation of histone modified. Further analysis about NR_026829 is taken to provide new target for early intervention on SM with animal model.

恶性肿瘤容易发生脊柱转移（Spinal Metastasis，SM），肺癌尤为多见，亚型肺腺癌占50%，机理不明。lncRNA在多层面调控基因表达，是否参与SM未见报道。前期芯片结果示lncRNANR_026829在转移瘤表达明显高于原发瘤。NR_026829与S100A9基因位点相邻，NR_026829沉默能抑制S100A9表达，显示S100A9可能为潜在作用靶点，免疫组化显示S100A9在转移瘤高表达。预实验提示NR_026829可能调控S100A9介导肺腺癌脊柱转移。本课题以免疫抑制细胞（MDSC）和循环肿瘤细胞(CTC)为研究对象，采用组蛋白修饰转录调控等分子生物学和免疫学手段，研究NR_026829通过调控S100A9直接趋化CTC脊柱转移、和间接募集MDSC形成免疫抑制微环境双重途径在SM中的机理；用脊柱转移瘤动物模型进一步分析NR_026829作用，为早期干预SM提供新靶点。

恶性肿瘤容易发生脊柱转移（Spinal Metastasis，SM），肺癌尤为多见，肺癌亚型中肺腺癌占50%，机理不明。lncRNA在多层面调控基因表达，是否参与SM未见报道。课题前期对临床原发及脊柱转移肺腺癌肿瘤标本芯片结果显示lncRNANR_026829在转移瘤表达明显高于原发瘤。进一步进行免疫组化、WB、PCR实验验证上述结果，显示lncRNANR_026829、S100A9在转移瘤高表达。生存分析表明lncRNANR_026829高表达患者生存期短。lncRNANR_026829与S100A9基因位点相邻，lncRNANR_026829沉默能抑制S100A9表达，提示S100A9可能为潜在作用靶点，通过RNA-pulldown及建立过表达、敲低细胞证实，lncRNANR_026829可促进S100A9表达。进一步实验证实，lncRNANR_026829、S100A9可抑制肺腺癌凋亡、促进肺腺癌增殖。预实验提示lncRNANR_026829可能调控S100A9介导肺腺癌脊柱转移，利用上述细胞系构建肺腺癌脊柱转移小鼠模型证实，lncRNANR_026829可促进S100A9表达可促进肺腺癌细胞脊柱转移。本课题以免疫抑制细胞（MDSC）和循环肿瘤细胞(CTC)为研究对象，采用组蛋白修饰转录调控等分子生物学和免疫学手段，研究lncRNANR_026829通过调控S100A9直接趋化CTC脊柱转移、和间接募集MDSC形成免疫抑制微环境双重途径在SM中的机理；用脊柱转移瘤动物模型进一步分析lncRNANR_026829作用，为早期干预SM提供新靶点。