The study shows that a natural antimicrobial peptide called LL‑37, when released by immune cells (macrophages), can make colon cancer cells grow faster by turning on a growth‑promoting pathway. Blocking LL‑37 stopped this effect, suggesting that higher LL‑37 levels might be risky for colon cancer.

<b>Objective:</b> To investigate the effect and molecular mechanism of antimicrobial peptide LL-37 secreted by stromal cells on the growth of colorectal cancer cells. <b>Methods:</b> Colorectal cancer cells SW480 or HCT116 were co-cultured with human macrophages using Transwell(&#xae;) maxicell inserts to mimic the tumor microenvironment. The effect of macrophages on the proliferation of colorectal cancer cells was detected by Bromodeoxyuridine and enzyme-linked immunosorbent assay (BrdU-ELISA). The expression of LL-37 mRNA and protein in macrophages and colorectal cancer cells was evaluated by reverse transcription-real-time quantitative PCR (RT-qPCR) and Western blot. LL-37 neutralizing antibody was added to abrogate the LL-37 activation. Additionally, macrophages were transfected with LL-37 shRNA plasmids to inhibit LL-37 expression. And then, the proliferation of colorectal cancer cells was observed. Furthermore, the growth-related signaling pathways were detected by Western blot. <b>Results:</b> The BrdU-ELISA results showed that the absorbance of SW480 cells increased from 1.072&#xb1;0.097 to 5.121&#xb1;0.407 after co-culture (<i>P</i>&lt;0.001), and that of HCT116 cells increased from 1.229&#xb1;0.073 to 3.495&#xb1;0.228 (<i>P</i>&lt;0.001). RT-qPCR results showed that LL-37 mRNA expression in macrophages significantly increased from 2.682&#xb1;0.191 to 6.117&#xb1;0.768 after co-incubation (<i>P</i>&lt;0.05), whereas that in SW480 had no significant difference. Consistently the protein expression of LL-37 in macrophages was significantly increased by Western blot, while it did not change in SW480. The proliferation rate of SW480 cells was repressed by adding LL-37 neutralizing antibody or LL-37 shRNA plasmid. Furthermore, Western blot analysis showed that the expression of non-phosphorylated (activated) &#x3b2;-catenin and its target genes cyclin D1 as well as c-myc were distinctly increased in co-cultured SW480 cells, which could be reversed by anti-LL-37 antibodies. <b>Conclusion:</b> Macrophages promote the in vitro proliferation of colorectal cancer cells by enhancing the expression and secretion of antimicrobial peptides LL-37, and it seems that LL-37 activates colorectal cancer cells via Wnt/&#x3b2;-catenin pathway.