Cathelicidin hCAP18/LL-37 promotes cell proliferation and suppresses antitumor activity of 1,25(OH)2D3 in hepatocellular carcinoma

Abstract

Cathelicidin hCAP18/LL-37 can resist infection from various pathogens and is an essential component of the human immune system. Accumulating evidence has indicated that hCAP18/LL-37 plays a tissue-specific role in human cancer. However, its function in hepatocellular carcinoma (HCC) is poorly understood. The present study investigated the effects of hCAP18/LL-37 on HCC in vitro and in vivo. Results showed that hCAP18/LL-37 overexpression significantly promoted the proliferation of cultured HCC cells and the growth of PLC/PRF-5 xenograft tumor. Transcriptome sequencing analyses revealed that the PI3K/Akt pathway was the most significant upregulated pathway induced by LL-37 overexpression. Further analysis demonstrated that hCAP18/LL-37 stimulated the phosphorylation of EGFR/HER2 and activated the PI3K/Akt pathway in HCC cells. Furthermore, stronger EGFR/HER2/Akt signals were observed in the PLC/PRF-5LL-37 xenograft tumor. Interestingly, even though the expression of hCAP18/LL-37 was significantly downregulated in HCC cells and tumors, 1,25(OH)2D3 treatment significantly upregulated the hCAP18/LL-37 level both in HCC cells and xenograft tumors. Moreover, 1,25(OH)2D3 together with si-LL-37 significantly enhanced the antitumor activity of 1,25(OH)2D3 in the PLC/PRF-5 xenograft tumor. Collectively, these data suggest that hCAP18/LL-37 promotes HCC cells proliferation through stimulation of the EGFR/HER2/Akt signals and appears to suppress the antitumor activity of 1,25(OH)2D3 in HCC xenograft tumor. This implies that hCAP18/LL-37 may be an important target when aiming to improve the antitumor activity of 1,25(OH)2D3 supplementation therapy in HCC.

Renovation as innovation: Repurposing human antibacterial peptide LL-37 for cancer therapy

“…However, contradictory results have been shown for LL-37 linked to cancers in different models. The existing data indicate that LL-37 can exert a tumorigenic effect in some cancers, including lung cancer, breast cancer, ovarian cancer, melanoma, prostate cancer, liver cancer, and skin squamous cell carcinoma ( Coffelt et al, 2009 ; Cha et al, 2016 ; Muñoz et al, 2016 ; Wang et al, 2017 ; Habes et al, 2019 ; Jiang et al, 2020 ; Ding et al, 2021 ; Zhang et al, 2022 ). Mechanistically, 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 ( Ji et al, 2019 ).…”

“…A number of studies have reported that LL-37 exerts a diverse range of pleiotropic attributes including antimicrobial activities, immunity, angiogenesis, wound repair, and bone tissue engineering ( Tjabringa et al, 2003 ; Elssner et al, 2004 ; Bucki et al, 2010 ; Pfosser et al, 2010 ; Ramos et al, 2011 ; Liu et al, 2018 ; Mitchell et al, 2022 ). However, different from its traditional roles, emerging evidence from cancer biology studies suggests that LL-37 might promote or inhibit tumor progression ( Ren et al, 2012 ; Piktel et al, 2016 ; Chen et al, 2018 ; Jiang et al, 2020 ; Chen et al, 2021 ; Vitale et al, 2021 ; Kiatsurayanon et al, 2022 ; Zhang et al, 2022 ). LL-37 plays an important and complex role in the regulation of different human cancers.…”

Cathelicidin LL-37 promotes EMT, migration and metastasis of hepatocellular carcinoma cells in vitro and mouse model

“…Our previous research demonstrated that hCAP18/LL-37 has a promotional effect on HCC cell proliferation and tumor growth both in vitro and in vivo [ 19 ]. Furthermore, hCAP18/LL-37 expression can be significantly induced by 1,25(OH) 2 D 3 in HCC cells and in xenograft tumor tissue, which in turn suppresses the antitumor growth activity of 1,25(OH) 2 D 3 in HCC xenograft tumors.…”

Expression and significance of serum vitamin D and LL-37 levels in infants with bacterial pneumonia

“…25(OH)D produces antimicrobial peptides, including human antimicrobial peptide LL-37 and human β-defensin-2, by activating vitamin D receptors and binding to vitamin D effector element target genes during pathogen infection (4). LL-37 is the only human endogenous antimicrobial peptide in the cathelicidin family that has been discovered so far (5), and it shows a wide range of antibacterial activity against bacteria, viruses, and fungi (6) along with immunomodulatory and chemotactic effects (7,8), it is named LL -37 because it contains two lysine residues (L) before the N-terminus, and consists of 37 amino acids (9). The promoter region of LL -37 gene contains a TAAA sequence, an interleukin 6 nuclear factor -6 (NF -IL -6) binding site, and three acute phase response factors (APRF), which can bind to inflammatory factors, thereby increasing LL -37 gene expression levels (10).…”