肺癌是全世界癌症相关死亡的主要原因。KRAS是肺癌主要致癌驱动因子，可以通过基因突变或扩增激活，但长链非编码RNA（lncRNA）是否调节其激活仍未知。通过增加和减少功能方法，我们发现KRAS诱导的lncRNA HIF1A-As2在非小细胞肺癌（NSCLC）的体外和体内需要细胞增殖、上皮间质转化（EMT）和肿瘤扩散。HIF1A-As2转录谱分析的综合分析表明，HIF1A-As2以转录方式调节基因表达，尤其是调节转录因子基因，包括MYC。机制上，HIF1A-As2通过在MYC启动子上招募DHX9来表观上激活MYC，从而刺激MYC和其靶基因的转录。此外，KRAS通过诱导MYC促进HIF1A-As2的表达，表明HIF1A-As2和MYC形成双重调节环以加强肺癌的细胞增殖和肿瘤转移。HIF1A-As2的抑制者LNA GapmeR反义寡核苷酸（ASO）可以显着提高PDX和KRASLSLG12D驱动的肺肿瘤对10058-F4（MYC特异性抑制剂）和顺铂治疗的敏感性。©2023.作者。

Lung cancer is the leading cause of cancer-related deaths worldwide. KRAS is the main oncogenic driver in lung cancer that can be activated by gene mutation or amplification, but whether long non-coding RNAs (lncRNAs) regulate its activation remains unknown. Through gain and loss of function approaches, we identified that lncRNA HIF1A-As2, a KRAS-induced lncRNA, is required for cell proliferation, epithelial-mesenchymal transition (EMT) and tumor propagation in non-small cell lung cancer (NSCLC) in vitro and in vivo. Integrative analysis of HIF1A-As2 transcriptomic profiling reveals that HIF1A-As2 modulates gene expression in trans, particularly regulating transcriptional factor genes including MYC. Mechanistically, HIF1A-As2 epigenetically activates MYC by recruiting DHX9 on MYC promoter, consequently stimulating the transcription of MYC and its target genes. In addition, KRAS promotes HIF1A-As2 expression via the induction of MYC, suggesting HIF1A-As2 and MYC form a double-regulatory loop to strengthen cell proliferation and tumor metastasis in lung cancer. Inhibition of HIF1A-As2 by LNA GapmeR antisense oligonucleotides (ASO) significantly improves sensitization to 10058-F4 (a MYC-specific inhibitor) and cisplatin treatment in PDX and KRASLSLG12D-driven lung tumors, respectively.© 2023. The Author(s).