The Role of PLIN3 in Prognosis and Tumor-Associated Macrophage Infiltration: A Pan-Cancer Analysis

Shaohua Yang,1– 3,* Hejie Liu,4,* Youbin Zheng,5,* Hongyu Chu,6 Zhuming Lu,4 Jie Yuan,1,2 Shengshan Xu4 1Department of General Surgery, Foshan Clinical Medical School, Guangzhou University of Chinese Medicine, Foshan, Guangdong, People’s Republic of China; 2Department of General Surgery, Foshan Fosun Chancheng Hospital, Foshan, Guangdong, People’s Republic of China; 3Institute of Gastroenterology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 4Department of Thoracic Surgery, Jiangmen Central Hospital, Jiangmen, Guangdong, People’s Republic of China; 5Department of Radiology, Jiangmen Wuyi Hospital of Traditional Chinese Medicine, Jiangmen, Guangdong, People’s Republic of China; 6Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie Yuan, Email [email protected] Shengshan Xu, Email [email protected]: Nucleolar and spindle-associated protein 1 (PLIN3), a member of the perilipin family, plays a critical role in lipid droplet dynamics and is implicated in promoting tumor progression across several cancers. However, its influence on the tumor immune microenvironment and its potential as a prognostic indicator regarding immunotherapy responses have yet to be systematically evaluated. This study leverages data retrieved from multiple databases to address these questions.Methods: PLIN3 mRNA and protein expressions were analyzed across a diverse range of normal and cancerous tissues, utilizing data retrieved from multiple databases. The potential of PLIN3 as a diagnostic and prognostic biomarker in cancers was assessed. Advanced computational algorithms were employed to examine the impact of PLIN3 on immune cell infiltration. The association between PLIN3 expression and the presence of M2 macrophages was validated through analyses incorporating bulk and single-cell transcriptomics, spatial transcriptomics, and multicolor fluorescence staining techniques. Furthermore, the effects of PLIN3 on tumor malignancy and growth were investigated in vitro in lung adenocarcinoma (LUAD) cells. Potential compounds targeting PLIN3 were identified using the Connectivity Map (cMap) web tool, and their efficacy was further assessed through molecular docking.Results: PLIN3 was predominantly upregulated in various cancers, correlating with adverse prognostic outcomes. A strong positive association was observed between PLIN3 levels and M2 macrophage infiltration in several cancer types, establishing it as a potential pan-cancer marker for M2 macrophage presence. This was confirmed by integrative multi-omics analysis and multiple fluorescence staining. Additionally, PLIN3 knockdown in LUAD cells diminished their malignant traits, resulting in decreased proliferation and migration. In LUAD, clofibrate was identified as a potential inhibitor of PLIN3’s pro-oncogenic functions.Conclusion: PLIN3 may serve as a potential biomarker and oncogene, particularly in LUAD. It plays a key role in mediating M2 macrophage infiltration in various cancers and presents a promising immunotherapeutic target.Keywords: pan-cancer analysis, M2 macrophage, biomarker, prognosis, immunotherapy