Suppression of tumorigenesis in LUAD by LRP1B through regulation of the IL-6-JAK-STAT3 pathway

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-6JAK-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.

Automated summary

This study found that the expression of LRP1B was lower in LUAD tissues compared to normal tissues, and knockdown of LRP1B increased the malignancy of LUAD cells. Genomic analysis showed that low-level expression of LRP1B was associated with genomic instability and aneuploidy. Enrichment analysis of transcriptomic data revealed the activation of IL-6-JAK-STAT3, chemokine, cytokine, and other inflammation signaling pathways due to low expression of LRP1B. Furthermore, downregulation of LRP1B mRNA upregulated the activity of the IL-6-JAK-STAT3 pathway and promoted the secretion of IL-6 and IL-8. Overall, this study highlights LRP1B as a tumor suppressor gene and its role in promoting malignant progression in LUAD through the IL-6-JAK-STAT3 pathway.