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Suppression of tumorigenesis in LUAD by LRP1B through regulation of the IL-6-JAK-STAT3 pathway
Chunshui Ye1, Wei Chong1,2,3, Yuan Liu1
1Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University Jinan, Shandong, China.
Abstract:
Lung adenocarcinoma (LUAD) is the most common type of lung cancer. LRP1B was initially identified as a cancer suppressor in several cancers. However, the potential biological phenotypes and molecular mechanisms of LRP1B in LUAD have not been fully investigated. In our study, we showed that the expression of LRP1B in LUAD tissues was lower than that in normal tissues. Knockdown of LRP1B markedly enhanced malignancy of LUAD cells. Genomic analysis indicated that the population expressing low-levels of LRP1B had higher genomic instability, which accounted for a larger proportion of aneuploidy and inflammation subtyping. Enrichment analysis of bulk and cell-line transcriptomic data both showed that the low expression of LRP1B could induce the activation of IL-6-JAK-STAT3, chemokine, cytokine, and other inflammation signaling pathways. Moreover, our findings revealed that knockdown LRP1B enhanced the secretion of IL-6 and IL-8, as confirmed by ELISA assays. Further validation using PCR and WB confirmed that downregulation of LRP1B mRNA significantly upregulated the activity of the IL-6-JAK-STAT3 pathway. Collectively, this study highlights LRP1B as a tumor suppressor gene and reveals that LRP1B knockdown promotes malignant progression in LUAD by inducing inflammation through the IL-6-JAK-STAT3 pathway.
Insights
Low expression of LRP1B enhances lung adenocarcinoma (LUAD) malignancy by activating inflammation via the IL-6-JAK-STAT3 pathway. This study identifies LRP1B as a tumor suppressor in LUAD, crucial for genomic stability.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Lung adenocarcinoma (LUAD) is a prevalent cancer type.
- LRP1B is recognized as a potential cancer suppressor.
- The role of LRP1B in LUAD progression remains underexplored.
Purpose of the Study:
- To investigate the biological functions and molecular mechanisms of LRP1B in LUAD.
- To determine the impact of LRP1B expression levels on LUAD cell malignancy.
- To elucidate the signaling pathways influenced by LRP1B in LUAD.
Main Methods:
- Comparative analysis of LRP1B expression in LUAD and normal tissues.
- Experimental manipulation of LRP1B expression (knockdown) in LUAD cells.
- Genomic instability assessment, transcriptomic data analysis (bulk and cell-line), and pathway enrichment analysis.
- Validation of signaling pathway activation using ELISA, PCR, and Western Blot (WB).
Main Results:
- LRP1B expression is significantly lower in LUAD tissues compared to normal tissues.
- LRP1B knockdown increases LUAD cell malignancy and genomic instability, correlating with aneuploidy and inflammation.
- Downregulation of LRP1B activates inflammation-related pathways, including IL-6-JAK-STAT3, and elevates IL-6 and IL-8 secretion.
Conclusions:
- LRP1B functions as a tumor suppressor gene in LUAD.
- Reduced LRP1B expression promotes LUAD progression by inducing inflammation through the IL-6-JAK-STAT3 signaling pathway.
- LRP1B status may serve as a potential biomarker or therapeutic target in LUAD.
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