LncRNA MIR22HG 结合 YBX1 调控肺腺癌增殖的分子机制研究

At present, many studies have found that lncRNAs are abnormally expressed in tumors proliferation, but the mechanism of proliferation in lung adenocarcinoma is not clear. Our previous study found that 1) lncRNA MIR22HG overexpression was a good prognostic indicator of lung adenocarcinoma; 2) knocking down MIR22HG promoted the proliferation of lung adenocarcinoma cells; 3) RIP test verified that YBX1 protein binds to MIR22HG. Therefore, we proposed that the binding of lncRNA MIR22HG to YBX1 regulates the proliferation of lung adenocarcinoma. In order to verify this hypothesis, this project carried out the following experiments: 1) overexpression of MIR22HG to clarify its relationship with lung adenocarcinoma cell proliferation; 2) the use of GST pulldown and protein spectrum analysis techniques to identify the YBX1 binding protein and verification that MIR22HG binding YBX1 regulates the proliferation of lung adenocarcinoma through the binding protein; 3) in vivo experiments to confirm that MIR22HG overexpression inhibits lung adenocarcinoma proliferation. This study further enriches the molecular mechanism of lung adenocarcinoma proliferation, and provides new ideas and new targets for lung adenocarcinoma clinical treatment and prevention.

目前许多研究发现lncRNAs在肿瘤组织增殖方面表达异常，但其影响肺腺癌增殖的分子机制尚不清楚。我们研究小组在前期研究中发现：1) MIR22HG低表达是肺腺癌患者预后差的一个重要生物指标；2) 通过RNAi基因沉默MIR22HG后，肺腺癌细胞增殖明显加快；3) RIP实验表明MIR22HG与YBX1结合。因此，我们提出“lncRNA MIR22HG结合YBX1调控肺腺癌增殖”的假说。为了验证该假说，本项目将开展以下实验: 1) 通过过表达MIR22HG，进一步明确其与肺腺癌细胞增殖的关系；2) 通过GST pulldown、蛋白质谱分析等技术发现与YBX1相互结合的蛋白，并验证MIR22HG结合YBX1是否通过相互结合蛋白调控肺腺癌细胞的增殖；3) 动物实验验证MIR22HG过表达抑制肺腺癌的增殖。通过本项目研究，进一步了解肺腺癌增殖的分子机制，为肺腺癌临床治疗提供新思路和新靶点。

长链非编码RNA（lncRNA）MIR22HG先前已被鉴定为肝细胞癌中的预后标志物。在这里，我们对来自RNA-seq数据的lncRNA表达谱进行了综合分析，发现MIR22HG在肺癌中发挥了类似的作用。对918例肺癌和正常肺组织以及肺癌细胞系的分析显示，MIR22HG在肺癌中显着下调；这种表达下降与患者生存率低有关。MIR22HG结合并稳定了YBX1蛋白。沉默MIR22HG通过致癌基因YBX1，MET和p21的失调触发细胞存活和细胞死亡信号传导。在这个MIR22HG网络中，p21通过促进肺癌细胞增殖和抗凋亡发挥了致癌作用。通过抑制人原发性肺肿瘤中的多个细胞周期相关基因所表明MIR22HG起到肿瘤抑制剂的作用。这些数据显示MIR22HG具有作为肺癌的新的诊断和预后标志物以及作为治疗靶标的潜力。