Myeloid cell-derived LL-37 promotes lung cancer growth by activating Wnt/β-catenin signaling

Abstract

Rationale : Antimicrobial peptides, such as cathelicidin LL-37/hCAP-18, are important effectors of the innate immune system with direct antibacterial activity. In addition, LL-37 is involved in the regulation of tumor cell growth. However, the molecular mechanisms underlying the functions of LL-37 in promoting lung cancer are not fully understood. Methods : The expression of LL-37 in the tissues and sera of patients with non-small cell lung cancer was determined through immunohistological, immunofluorescence analysis, and enzyme-linked immunosorbent assay. The animal model of wild-type and Cramp knockout mice was employed to evaluate the tumorigenic effect of LL-37 in non-small cell lung cancer. The mechanism of LL-37 involving in the promotion of lung tumor growth was evaluated via microarray analyses, recombinant protein treatment approaches in vitro , tumor immunohistochemical assays, and intervention studies in vivo . Results : LL-37 produced by myeloid cells was frequently upregulated in primary human lung cancer tissues. Moreover, its expression level correlated with poor clinical outcome. LL-37 activated Wnt/β-catenin signaling by inducing the phosphorylation of protein kinase B and subsequent phosphorylation of glycogen synthase kinase 3β mediated by the toll-like receptor-4 expressed in lung tumor cells. LL-37 treatment of tumor cells also decreased the levels of Axin2. In contrast, it elevated those of an RNA-binding protein (tristetraprolin), which may be involved in the mechanism through which LL-37 induces activation of Wnt/β-catenin. Conclusion : LL-37 may be a critical molecular link between tumor-supportive immune cells and tumors, facilitating the progression of lung cancer.

Cathelicidin Host Defense Peptides and Inflammatory Signaling: Striking a Balance

“…Furthermore, systems biology and biochemical studies on human CD14 + monocytes treated with LL-37 showed nearly 500 genes changing expression, reflecting the involvement of many of these pathways in chemokine induction in response to LL-37 (Mookherjee et al, 2009). Activation of Wnt/β-Catenin and PI3K/Akt signaling cascades elicited by LL-37 was also demonstrated in samples from non-small cell lung carcinoma patients (Ji et al, 2019) with a positive correlation between LL-37 concentration in tissues and relevant gene expression. Similarly, in the A549 pneumocyte cell line in vitro, LL-37 stimulated growth through a β-Catenindependent but TLR-independent manner (Ji et al, 2019).…”

PLAC8 inhibits oral squamous cell carcinogenesis and epithelial-mesenchymal transition via the Wnt/β-catenin and PI3K/Akt/GSK3β signaling pathways

“…Akt phosphorylation of GSK3β may lead to stabilization of β-catenin and accumulation of nuclear β-catenin ( 22 ). Numerous studies have suggested that Wnt signaling cross-talks with the PI3K/Akt signaling pathway ( 17 , 23 ). Therefore, the present study investigated whether PLAC8 could also contribute to the PI3K/Akt/GSK3β signaling pathway in OSCC.…”

“…Additionally, β-catenin, as the main component of the Wnt/β-catenin signaling pathway, induces the transcription of c-Myc and cyclin D1 that stimulates cancer cell proliferation ( 22 ). It has been previously demonstrated that the Wnt/β-catenin signaling pathway is important in cathelicidin-promoted growth of lung and colon cancer cells ( 19 , 23 , 34 ). In the present study, PLAC8 overexpression downregulated c-Myc and cyclin D1 expression.…”

Glycogen synthase kinase-3β: a promising candidate in the fight against fibrosis

“…As a multifunctional protein, β-Catenin plays an essential role in the process of cell proliferation, differentiation, and apoptosis 56 , 57 . The transfer of β-Catenin into the nucleus after accumulation in the cytoplasm is an important step in causing fibrosis.…”