Background: Bone marrow mesenchymal stem cell-derived exosomes (BMSC-exo) can promote the metastasis of lung cancer (LC) under hypoxic conditions, but the mechanism needs to be explored. This study aims to investigate the role of adenosylhomocysteinase (AHCY) derived from hypoxia BMSC-exo in the development of LC.

Methods: BMSC-exo under normoxic or hypoxic conditions were identified by transmission electron microscope. The relationship between AHCY and methylcrotonyl-CoA carboxylase subunit 2 (MCCC2) was analyzed by bioinformatics analysis. The expression levels of AHCY in hypoxia BMSC-exo or LC cells treated with hypoxia BMSC-exo were determined by quantitative real-time polymerase chain reaction (qRT-PCR). The viability, migration, invasion, and the expression levels of N-cadherin, E-cadherin and extracellular regulated protein kinases (ERK) pathway-related proteins in LC cells transfected with MCCC2 overexpression plasmid and AHCY specific small interfering RNA (siAHCY) as well as treated with normal/hypoxia BMSC-exo were determined using cell counting kit-8 (CCK-8), transwell assay and Western blotting.

Results: AHCY was highly expressed in hypoxia BMSC-exo (p < 0.001). With the increase in the exosome release inhibitor GW4869 concentration, the total amount of AHCY protein detected in exosomes isolated from equal volumes of conditioned medium derived from hypoxic BMSCs gradually decreased (p < 0.001). Hypoxia BMSC-exo facilitated cell viability, migration, invasion and the expressions of N-cadherin and MCCC2, yet inhibited E-cadherin expression, while these effects were reversed by siAHCY (p < 0.05). AHCY and MCCC2 are positively correlated in LC. SiAHCY downregulated the ratio of p-ERK1/2/ERK1/2, whereas this effect was reversed by MCCC2 overexpression (p < 0.05).

Conclusions: Hypoxia BMSC-exo carries AHCY to up-regulate MCCC2 expression in LC cells, thereby activating the ERK pathway to facilitate the development of LC. This study identifies a novel exosome-mediated mechanism in the tumor microenvironment and highlights potential therapeutic targets for intervention.