Respiratory Syncytial Virus Enhances SIRT2 Expression Through Wnt/β-Catenin Signaling to Promote Lung Cancer Progression

Abstract

Background: The Wnt/β-catenin signaling pathway is a key regulator of cellular processes, with its dysregulation implicated in various cancers, including lung cancer. Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, has emerged as a potential downstream target of this pathway. Objectives: The present study explores the regulation of SIRT2 expression by Wnt/β-catenin signaling and respiratory syncytial virus (RSV) infection, and their roles in lung cancer progression. Methods: Five hundred forty-nine lung cancer cells and MRC5 normal lung cells were used to investigate the interplay between RSV infection, Wnt/β-catenin signaling, and SIRT2. Expression levels of SIRT2 and β-catenin were assessed by Western blotting, real-time PCR, and confocal microscopy. The impact of Wnt3a (activator), XAV939 (inhibitor), and SIRT2 modulation on cell proliferation, oncogenic marker expression, and apoptosis were evaluated. Results: Wnt3a treatment increased SIRT2 and β-catenin expression at transcriptional and protein levels in A549 cells, while XAV939 reversed this effect. The RSV infection synergistically enhanced SIRT2 expression, with Wnt3a amplifying the effect and XAV939 inhibiting it. Confocal microscopy revealed RSV-induced cytoplasmic accumulation of SIRT2 and β-catenin. The SIRT2 overexpression augmented RSV- and Wnt3a-mediated proliferation and increased cyclin D1 expression, while SIRT2 knockdown suppressed these effects. Sirtuin 2 and Wnt/β-catenin signaling synergistically upregulated Ki-67, Snail, and c-Myc, promoting tumor progression. SIRT2 enhanced anti-apoptotic markers (Bcl-2) and inhibited pro-apoptotic markers (cleaved caspase-3 and PARP). The SIRT2 knockdown reversed these effects, inducing apoptosis. Conclusions: The RSV infection activates the Wnt/β-catenin pathway to upregulate SIRT2, which promotes lung cancer progression by enhancing cell proliferation, oncogenic marker expression, and anti-apoptotic activity. Targeting SIRT2 and its regulatory pathways offers a promising therapeutic strategy for combating lung cancer.