VPS35 promotes tumor proliferation and migration through the PPARs-ACSL1/4 pathway in lung adenocarcinoma

Objective: Globally, lung Cancer represents the most incident and lethal malignancy, among which lung adenocarcinoma (LUAD) constitutes 40-60% of cases and exhibits rising prevalence. Advanced LUAD is refractory to current chemotherapeutic and targeted therapies, necessitating novel therapeutic targets. While the role of VPS35 in many cancers has been reported, its exact contribution to LUAD tumorigenesis has not been fully elucidated. We intended to clarify biological roles of VPS35 in LUAD to explore its potential clinical translational value.

Methods: Immunohistochemistry (IHC) on LUAD tissue microarrays was performed to assess VPS35 expression and clinical relevance. In vitro functional assays were conducted in both VPS35-knockdown (shRNA) and VPS35-overexpressing LUAD cell lines. A subcutaneous xenograft tumor model was established to evaluate the in vivo role of VPS35 in regulating LUAD growth, and a tail vein injection lung metastasis model was further used to determine its function in promoting tumor metastasis. Bioinformatic analyses and western blotting were integrated to identify and verify the PPARs-ACSL1/4 signaling pathway as the downstream target of VPS35. Lipid metabolism related functional assays were performed to explore the regulatory effect of VPS35 on lipid metabolic reprogramming. Co-immunoprecipitation (Co-IP) was performed to verify the physical interaction between VPS35 and p300, a co-activator of the PPARs transcription complex.

Results: VPS35 was markedly overexpressed in LUAD tissues compared with adjacent normal tissues. VPS35 knockdown inhibited LUAD cell proliferation, migration, and enhanced Apoptosis. Enrichment analysis of TCGA data revealed enrichment of the fatty acid metabolic pathway in the VPS35 high-expression group. Mechanistically, VPS35 modulates the activity of the PPARs transcription complex through direct interaction with p300, a transcriptional co-activator, thereby governing the PPARs-ACSL1/4 signaling cascade to drive lipid metabolic reprogramming and tumor progression.

Conclusion: This study clarifies VPS35's role in driving LUAD progression via the PPARs-ACSL1/4 pathway, indicating its promise as a therapeutic clue for LUAD.