期刊
THERANOSTICS
卷 9, 期 8, 页码 2209-2223出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.30726
关键词
LL-37; lung cancer; tumor microenvironment; Wnt/beta-catenin
资金
- National Natural Science Foundation of China [81472179, 81873975]
- Excellent Academic Leader Training Program of Shanghai Health System [2018BR31]
- Three-Year Action Plan for Promoting Construction of Public Health (2015-2017) [15GWZK0301]
- Fundamental Research Funds for the Central Universities [22120170071]
- Clinical Research and Cultivation Project of Shanghai Tongji Hospital [ITJ(ZD)1803]
- Innovation Group Project of Shanghai Municipal Health Commission [2019CXJQ03]
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/beta-catenin signaling by inducing the phosphorylation of protein kinase B and subsequent phosphorylation of glycogen synthase kinase 3 beta 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/beta-catenin. Conclusion: LL-37 may be a critical molecular link between tumor-supportive immune cells and tumors, facilitating the progression of lung cancer.
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