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

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.