STAT3激活LINC01001募集IGF2BP2促进ALK阳性非小细胞肺癌增殖的机制研究

There is evidence showed that long noncoding RNAs(lncRNAs) involve in tumor proliferation, apoptosis and differentiation. pSTAT3 is a key underlying target of ALK in NSCLC. Here, we analyzed pSTAT3 ChIP-seq data and found that pSTAT3 is significantly enriched in LINC01001 promoter regions. Knockdown of LINC01001 expression significantly inhibited NSCLC cells proliferation and induced cell apoptosis. Bioinformatics analysis and RIP assays confirmed that LINC01001 can interact with the m6A reader IGF2BP2. Further next generation sequencing analysis showed that MYC is one of the LINC01001 and IGF2BP2 target. Therefore, we propose our hypothesis that pSTAT3 activated LINC01001 expression in ALK-positive NSCLC, and increased LINC01001 promotes NSCLC development by interacting with IGF2BP2 and promoting MYC expression. Further mechanistic investigation will be performed to determine our hypothesis. Our study will further our understanding of the molecular mechanism of ALK-positive NSCLC development and progression, and may provide new targets for ALK-positive NSCLC patients.

长非编码RNA与肿瘤增殖、凋亡、分化密切相关，但其在ALK融合阳性NSCLC中的作用尚不完全清楚。pSTAT3是ALK下游的重要分子，本课题组前期通过分析pSTAT3的ChIP数据，发现ALK阳性NSCLC细胞中pSTAT3能结合到LINC01001启动子区促进其表达；干扰LINC01001表达显著抑制NSCLC细胞增殖，并诱导细胞凋亡。进一步生物信息学分析及RIP实验证实LINC01001与m6A阅读器IGF2BP2结合，测序分析发现MYC为LINC01001与IGF2BP2的靶基因。据此提出假设：在ALK阳性NSCLC中pSTAT3激活LINC01001的表达，LINC01001通过募集IGF2BP2维持MYC的稳定，促进ALK阳性NSCLC细胞的增殖。本课题组将通过扩大临床样本证实上述假设，丰富ALK阳性NSCLC发生机制的认知，为ALK阳性NSCLC潜在分子靶向治疗提供新依据。

长非编码RNA与肿瘤增殖、凋亡、分化密切相关，但其在ALK融合阳性NSCLC中的作用尚不完全清楚。我们的研究结果表明，LINC01001在克唑替尼耐药株NSCLC细胞中高表达，并与NSCLC患者的预后不良相关。抑制LINC01001可抑制了NSCLC的克唑替尼耐药性。LINC01001与IGF2BP2相互作用，抑制IGF2BP2可抑制NSCLC的克唑替尼耐药性。IGF2BP2与MYC的mRNA相互作用,LINC01001通过调节IGF2BP2/MYC轴来调节NSCLC的克唑替尼耐药性。本课题丰富ALK阳性NSCLC发生机制的认知，为ALK阳性NSCLC潜在分子靶向治疗提供新依据。