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

作者：Ping Ji, Yongxin Zhou, Yibao Yang, Junlu Wu, Hao Zhou, Wenqiang Quan, Junjun Sun, Yiwen Yao, Anquan Shang, Chenzheng Gu, Bingjie Zeng, Jenni Firrman, Weidong Xiao, Robert Bals, Zujun Sun, Dong Li · 发表于：Theranostics · 年份：2019 · DOI：10.7150/thno.30726 · 被引用次数：46 · 研究领域：Antimicrobial Peptides and Activities、Immune Response and Inflammation、S100 Proteins and Annexins

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/-catenin signaling by inducing the phosphorylation of protein kinase B and subsequent phosphorylation of glycogen synthase kinase 3 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 ...