JunB通过调控假基因DUXAP10增强非小细胞肺癌吉非替尼耐药的研究

Non-small cell lung cancer EGFR-TKI acquired resistance is currently the urgent problem to be solved. The mechanism of pseudogene and NSCLC gefitinib drug resistance has not been reported. We found that the expression of pseudogene DUXAP10 was higher in NSCLC tissues by GEO database analysis. Further studies have shown that DUXAP10 is highly expressed in gefitinib-acquired drug-resistant tissues and drug-resistant cells. Bioinformatics analysis showed that the DUXAP10 promoter region contained the JunB binding sites, and the level of DUXAP10 decreased after knock down of JunB. RIP assays confirmed that DUXAP10 binds to the core subunit SUZ12 of the PRC2 complex. Gene chip analysis showed that FOXO3a expression was upregulated after interfering with DUXAP10 expression. Accordingly, the hypothesis is proposed : JunB promotes pseudogene DUXAP10 transcription, and binds SUZ12 which represses FOXO3a transcription by promoter methylation to enhance the gefitinib-resistance of NSCLC. We will confirm the above hypothesis by using RIP, ChIP, Pulldown and other techniques to provide a new target for reversing TKI acquired resistant therapy.

非小细胞肺癌EGFR-TKI获得性耐药是目前临床亟待解决的问题，假基因与NSCLC吉非替尼耐药的相关性研究尚未见报道。我们前期通过GEO数据库分析发现假基因DUXAP10在NSCLC癌组织中表达上调。进一步研究表明，DUXAP10在吉非替尼获得性耐药的组织及细胞中表达量均显著提高。生物信息学分析显示DUXAP10启动子区域含有JunB结合位点，干扰JunB后DUXAP10表达下调，RIP实验证实DUXAP10与PRC2复合物核心亚基SUZ12绑定。基因芯片分析表明，干扰DUXAP10表达后FOXO3a表达上调。据此提出假说：JunB促进假基因DUXAP10转录，通过绑定SUZ12介导FOXO3a启动子区的甲基化，进而抑制其转录，从而增强NSCLC吉非替尼耐药性。本课题组将通过临床样本验证，运用RIP、ChIP、Pulldown等技术证实上述假设，为逆转TKI获得性耐药的生物治疗提供依据。

非小细胞肺癌EGFR-TKI获得性耐药是目前临床亟待解决的问题，假基因与NSCLC吉非替尼耐药的相关性研究尚未见报道。我们前期通过GEO数据库分析发现假基因DUXAP10在NSCLC癌组织中表达上调。进一步研究表明，DUXAP10在吉非替尼获得性耐药的组织及细胞中表达量均显著提高。RIP实验证实DUXAP10与PRC2复合物核心亚基EZH2绑定。基因芯片分析表明，干扰DUXAP 10表达后OSA2表达上调。据此提出假说:UDXAP10通过绑定EZH2介导 OSA2启动子区的甲基化，进而抑制其转录，从而增强NSCLC吉非替尼耐药性。本课题组将通过临床样本验证，运用RIP、ChIP、Pulldown等技术证实上述假设，为逆转TKI获得性耐药的生物治疗提供依据。