Amine oxidase, copper containing 3 exerts anti-mesenchymal transformation and enhances CD4+ T-cell recruitment to prolong survival in lung cancer

Abstract

Lung cancer remains notorious for its poor prog- nosis. Despite the advent of tyrosine kinase inhibitors and immune checkpoint inhibitors, the probability of curing the disease in lung cancer patients remains low. Novel mecha- nisms and treatment strategies are needed to provide hope to patients. Advanced strategies of next generation sequencing (NGS) and bioinformatics were used to analyze normal and lung cancer tissues from lung cancer patients. Amine oxidases have been linked to leukocyte migration and tumorigenesis. However, the roles of amine oxidases in lung cancer are not well-understood. Our results indicated that amine oxidase, copper containing 3 (AOC3) was significantly decreased in the tumor tissue compared with the normal tissue, at both the mRNA and protein level, in the included lung cancer patients and public databases. Lower expression of AOC3 conferred a poorer survival probability across the different cohorts. Epigenetic silencing of AOC3 via miR-3691-5p caused tumor promotion and progression by increasing migration and epithe- lial-mesenchymal transition (EMT). Furthermore, knockdown of AOC3 caused less CD4+ T-cell attachment onto lung cancer cells and reduced transendothelial migration in vitro, as well as reducing CD4+ T-cell trafficking to the lung in vivo. In conclu- sion, the present study revealed that downregulation of AOC3 mediated lung cancer promotion and progression, as well as decrease of immune cell recruitment. This novel finding could expand our understanding of the dysregulation of the tumor immune microenvironment and could help to develop a novel strategy for the treatment of lung cancer.