An inverse interaction between HOXA11 and HOXA11-AS is associated with cisplatin resistance in lung adenocarcinoma

Abstract

ABSTRACTHOXA11, which is a member of the homeobox (HOX) gene family, and its natural antisense transcript (NAT) HOXA11-AS have been reported to be closely related to the development of lung cancer. We aimed to investigate their specific roles in cisplatin (DDP) resistance in lung adenocarcinoma (LUAD). First, we found that HOXA11 is hypermethylated and significantly downregulated in a DDP-resistant A549 cell line (A549/DDP) and LUAD tissues, while the HOXA11-AS expression level is elevated. Although HOXA11 and HOXA11-AS mRNA overlap in the 5ʹ-untranslated region (5ʹ UTR) and share two CpG islands, DNA methylation only regulates the expression of HOXA11. Then, we found that HOXA11 and HOXA11-AS have an inverse interaction by transfecting their siRNAs and overexpression vectors into A549 and A549/DDP cells. A dual-luciferase reporter assay further confirmed that the overlapping 5ʹUTR is essential for the bidirectional regulation between HOXA11 and HOXA11-AS. Functional analysis showed that knockdown of HOXA11 expression in A549 cells induced DDP resistance and activated Akt/β-catenin signaling, while overexpression of HOXA11 in A549/DDP cells increased DDP sensitivity and inhibited Akt/β-catenin signaling. Moreover, HOXA11-AS knockdown in A549 cells increased DDP sensitivity and inhibited Akt/β-catenin signaling, while the overexpression of HOXA11-AS in A549/DDP cells induced DDP resistance and activated Akt/β-catenin signaling. In conclusion, our study demonstrates that the inverse interaction between HOXA11 and HOXA11-AS promotes DDP resistance in LUAD.