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CASQ2 alleviates lung cancer by inhibiting M2 tumor-associated macrophage polarization and JAK/STAT pathway
Yan Ding1, Xiaoliang Yuan1, Ying Wang1
1Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou City, Jiangxi Province, China.
Abstract:
Lung cancer (LC) is a major inducer of cancer-related death. We aim to reveal the effect of Calsequestrin2 (CASQ2) on macrophage polarization and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in LC. Hub genes were determined from protein-protein interaction networks based on GSE21933 and GSE1987 data sets using bioinformatic analysis. Expression of hub genes was verified by real-time quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, wound-healing, colony formation, and transwell assays were performed to assess the impact of CASQ2 on LC cells. A xenograft mouse model was evaluated using hematoxylin-eosin, immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining to investigate the effect of CASQ2 on LC. The role of CASQ2 in regulating macrophage polarization and JAK/STAT pathway was evaluated by western blot andRT-qPCR. We screened out 155 common differentially expressed genes in GSE21933 and GSE1987 data sets. Myomesin-2, tyrosine kinase, sex determining region Y-box 2, platelet and endothelial cell adhesion molecule 1, matrix metallopeptidase 9, claudin-5, caveolin-1, CASQ2, recombinant ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 (ATP2A2), and ankyrin repeat domain 1 were identified as the hub genes with high prediction value. CASQ2 was selected as a pivotal regulator of LC. In vitro experiments and xenograft models revealed that CASQ2 overexpression suppressed proliferation, colony formation, migration, invasion of LC cells, and tumor growth in vivo. Additionally, overexpression of CASQ2 promoted the expression of M1 macrophage markers (cluster of differentiation 80 [CD80], interleukin [IL]-12, inducible nitric oxide synthase [iNOS]), while decreasing the expression of M2 macrophage markers (CD163, IL-10, Arg1) in tumor-associated macrophages and xenograft tissues. Finally, we found that overexpression of CASQ2 inhibited JAK/STAT pathway. CASQ2 is a novel biomarker, which can alleviate LC via inhibiting M2 tumor-associated macrophage polarization and JAK/STAT pathway.
Insights
Calsequestrin2 (CASQ2) suppresses lung cancer (LC) progression by inhibiting M2 macrophage polarization and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. This discovery highlights CASQ2 as a potential therapeutic target for lung cancer treatment.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Lung cancer (LC) remains a leading cause of cancer-related mortality worldwide.
- Understanding the molecular mechanisms regulating LC progression and the tumor microenvironment is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the role of Calsequestrin2 (CASQ2) in modulating macrophage polarization and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in lung cancer.
- To identify key molecular regulators of lung cancer through bioinformatic analysis of gene expression datasets.
Main Methods:
- Bioinformatic analysis of GSE21933 and GSE1987 datasets to identify hub genes.
- In vitro assays (Cell Counting Kit-8, EdU, wound-healing, colony formation, Transwell) to assess CASQ2's effect on LC cells.
- In vivo xenograft mouse models with histological and molecular analyses (H&E, IHC, TUNEL, Western blot, RT-qPCR) to evaluate CASQ2's impact.
- Assessment of macrophage polarization markers (M1/M2) and JAK/STAT pathway activation.
Main Results:
- CASQ2 was identified as a pivotal hub gene in lung cancer.
- Overexpression of CASQ2 significantly suppressed LC cell proliferation, migration, invasion, and colony formation in vitro.
- In vivo, CASQ2 overexpression inhibited tumor growth and promoted M1 macrophage polarization while suppressing M2 polarization.
- CASQ2 overexpression led to the inhibition of the JAK/STAT signaling pathway.
Conclusions:
- CASQ2 acts as a tumor suppressor in lung cancer by inhibiting proliferation and metastasis.
- CASQ2 influences the tumor microenvironment by reprogramming tumor-associated macrophages towards an anti-tumorigenic M1 phenotype.
- CASQ2 alleviates lung cancer by suppressing M2 macrophage polarization and inhibiting the JAK/STAT pathway, suggesting its potential as a novel therapeutic biomarker.
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