Exosomal transfer of VPS9D1-AS1 induces M2 polarization to promote erlotinib resistance of LUAD cells via activation of the Wnt/β-catenin signaling pathway.

Tumor microenvironment (TME) is widely recognized as a critical effector in lung adenocarcinoma (LUAD) progression. Tumor-associated macrophages (TAMs) are the main components of TME. A substantial amount of evidence has revealed the correlation between TAMs and the survival of LUAD patients. In this study, we firstly proved that long non-coding RNA (lncRNA) VPS9 domain containing 1 antisense RNA 1 (VPS9D1-AS1) regulates erlotinib resistance in LUAD. The focus of this study is to investigate whether exosome-transmitted VPS9D1-AS1 influenced erlotinib resistance in LUAD through interacting with TAMs. Our study found that VPS9D1-AS1 could induce M2 macrophages polarization. Besides, we proved that exosomal transfer of VPS9D1-AS1 promoted M2 polarization. Moreover, exosomal transfer of VPS9D1-AS1 induce Wnt/β-catenin pathway activation by recruiting MYCN opposite strand (NCYM) to promote glycogen synthase kinase-3β (GSK-3β) ubiquitination and degradation. Meanwhile, exosomal transfer of VPS9D1-AS1 sequestered miR-532-3p to up-regulate catenin beta 1 (CTNNB1). Taken together, exosomal transfer of VPS9D1-AS1 induced M2 polarization to promote erlotinib resistance of LUAD cells through activating Wnt/β-catenin pathway.