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.
Highlights
Primary liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide in 2020, with ~906,000 new cases and 830,000 deaths [1]
Important primary vitamin D target gene in the VDR pathway, and peptide, hCAP18/LL-37 levels were detected in the culture hCAP18/LL-37 is induced by 1,25(OH)2D3 in several cell types, medium after pcDNA/hCAP18 transfections with different duraincluding various immune, epithelial, and some cancer cell tions
Expression of CAMP gene is decreased in human Hepatocellular carcinoma (HCC) tumor overexpression of hCAP18/LL-37 in PLC/PRF-5 and Huh7 cells led and cultured HCC cells to a significant enhancement of cell proliferation, as more EdU-Using the GEPIA and UALCAN databases, the hCAP18 mRNA level positive cells were observed (p < 0.01; Fig. 3A)
Summary
Primary liver cancer is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide in 2020, with ~906,000 new cases and 830,000 deaths [1]. Important primary vitamin D target gene in the VDR pathway, and peptide, hCAP18/LL-37 levels were detected in the culture hCAP18/LL-37 is induced by 1,25(OH)2D3 in several cell types, medium after pcDNA/hCAP18 transfections with different duraincluding various immune, epithelial, and some cancer cell tions. Results showed that both hCAP18 and LL-37 were detected [19, 20]. Colony hCAP18/LL-37 in human HCC utilizing in vitro and in vivo formation ability of PLC/PRF-5 and Huh cells was significantly functional assays. Expression of hCAP18/LL-37 in HCC cells promotes proliferation via cell cycle progression
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