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

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

  • Biochem Pharmacol. 2026 Jan;243(Pt 2):117537. doi: 10.1016/j.bcp.2025.117537.
Zhuoran Teng 1,  Jingyan Gao 2,  Chen Li 3,  Miao Wang 2,  Lan Li 2,  Yunhe Jv 2,  Fei Lu 2,  Yu Hou 4,  Yaoxiong Xia 5,  Yanping Gao 6,  Qiao Zhang 7
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China.
  • 2 Departments of Radiotherapy, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China.
  • 3 Department of Scientific Research, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China.
  • 4 Departments of Radiotherapy, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China. Electronic address: [email protected].
  • 5 Departments of Radiotherapy, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China. Electronic address: [email protected].
  • 6 Departments of Radiotherapy, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, Yunnan, China. Electronic address: [email protected].
  • 7 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan, China. Electronic address: [email protected].
PMID: 41207568 DOI: 10.1016/j.bcp.2025.117537
Abstract

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.

Keywords

Erlotinib resistance; Lung adenocarcinoma; M2 polarization; VPS9D1-AS1; Wnt/β-catenin.

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