假基因DUXAP8抑制EGR1、RHOB表达促进非小细胞肺癌侵袭转移的机制研究

Tumor cells invasion and metastasis is one of the major causes leading to the treatment fail in non small cell lung cancer (NSCLC) patients. There is evidence showed that pseudogenes involved in tumorigenesis and cancer cells metastasis. Here, we found that the pseudogene DUXAP8 expression is significantly up-regulated in NSCLC tissues by analyzing the microarray data from GEO datasets and TCGA sequencing data. Knockdown of its expression impaired NSCLC cells invasion ability and affected EMT related markers protein expression. RIP assays showed that DUXPA8 could directly bind with LSD1/CoREST complex. RNA sequencing in DUXAP8 knockdown A549 cells indicated that tumor suppressor EGR1 and RHOB is DUXAP8 potential underlying targets in NSCLC cells. Moreover, knockdown of LSD1 also increased EGR1 and RHOB expression. Therefore, we propose our hypothesis that increased DUXAP8 promotes NSCLC cells EMT process, invasion and metastasis by recruiting LSD1/CoREST to EGR1 and RHOB promoter regions and repressing their transcription. Further mechanistic investigation will be performed to determine our hypothesis by using RNA pulldown, ChIP et al. Technique. Our study will further our understanding of the molecular mechanism of NSCLC cells metastasis, and may provide new targets for NSCLC patients therapy.

复发转移是非小细胞肺癌（NSCLC）患者治疗失败的主要原因。假基因与肿瘤发生和转移密切相关，但目前文献报道甚少。我们通过分析GEO数据库NSCLC芯片和TCGA测序数据发现假基因DUXAP8在NSCLC组织中表达显著上调，组织样本中得到验证。干扰DUXAP8的表达显著抑制细胞侵袭能力，并影响EMT标记分子的表达。RIP实验证实DUXAP8与组蛋白去甲基化酶LSD1/CoREST复合体结合。RNA测序发现EGR1和RHOB是DUXAP8的靶基因，干扰LSD1亦能上调二者表达。据此提出假设：NSCLC中DUXAP8表达上调，并绑定LSD1/CoREST介导EGR1、RHOB启动子区的去甲基化抑制其转录，促进细胞的EMT和侵袭能力。本课题组将通过临床样本验证，运用RNA pulldown、ChIP等技术证实上述假设，丰富NSCLC复发转移分子机制的认知，为NSCLC临床的分子靶向治疗提供新依据。

复发转移是非小细胞肺癌（NSCLC）患者治疗失败的主要原因。假基因与肿瘤发生和转移密切相关，但目前文献报道甚少。我们通过分析GEO数据库NSCLC芯片和TCGA测序数据发现假基因DUXAP8在NSCLC组织中表达显著上调，组织样本中得到验证。干扰DUXAP8的表达显著抑制细胞侵袭能力，并影响EMT标记分子的表达。RIP实验证实DUXAP8与组蛋白去甲基化酶LSD1/CoREST复合体结合。RNA测序发现EGR1和RHOB是DUXAP8的靶基因，干扰LSD1亦能上调二者表达。据此提出假设：NSCLC中DUXAP8表达上调，并绑定LSD1/CoREST介导EGR1、RHOB启动子区的去甲基化抑制其转录，促进细胞的EMT和侵袭能力。本课题组将通过临床样本验证，运用RNA pulldown、ChIP等技术证实上述假设，丰富NSCLC复发转移分子机制的认知，为NSCLC临床的分子靶向治疗提供新依据。