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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-5^LL-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.

SUBMITTER: Zhang H

PROVIDER: S-EPMC8763942 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Cathelicidin hCAP18/LL-37 promotes cell proliferation and suppresses antitumor activity of 1,25(OH)<sub>2</sub>D<sub>3</sub> in hepatocellular carcinoma.

Zhang Huidan H Zhen Junai J Zhang Rong R Wanyan Yangke Y Liu Kehang K Yuan Xueli X Tao Liping L Chen Yuqing Y

Cell death discovery 20220117 1

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 c ...[more]

PMID: 35039485

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Project description:IntroductionHuman cathelicidin antimicrobial protein, hCAP18, and its C-terminal peptide LL-37 is a multifunctional protein. In addition to being important in antimicrobial defense, it induces chemotaxis, stimulates angiogenesis and promotes tissue repair. We previously showed that human breast cancer cells express high amounts of hCAP18, and hypothesised that hCAP18/LL-37 may be involved in tumour progression.MethodshCAP18 mRNA was quantified in 109 primary breast cancers and compared with clinical findings and ERBB2 mRNA expression. Effects of exogenous LL-37 and transgenic overexpression of hCAP18 on ErbB2 signalling were investigated by immunoblotting using extracts from breast cancer cell lines ZR75-1 and derivatives of MCF7. We further analysed the impact of hCAP18/LL-37 on the morphology of breast cancer cells grown in soft agar, on cell migration and on tumour development in severe combined immunodeficiency (SCID) mice.ResultsThe expression of hCAP18 correlated closely with that of ERBB2 and with the presence of lymph node metastases in oestrogen receptor-positive tumours. hCAP18/LL-37 amplified Heregulin-induced mitogen-activated protein kinase (MAPK) signalling through ErbB2, identifying a functional association between hCAP18/LL-37 and ErbB2 in breast cancer. Treatment with LL-37 peptide significantly stimulated the migration of breast cancer cells and their colonies acquired a dispersed morphology indicative of increased metastatic potential. A truncated version of LL-37 competitively inhibited LL-37 induced MAPK phosphorylation and significantly reduced the number of altered cancer cell colonies induced by LL-37 as well as suppressed their migration. Transgenic overexpression of hCAP18 in a low malignant breast cancer cell line promoted the development of metastases in SCID mice, and analysis of hCAP18 transgenic tumours showed enhanced activation of MAPK signalling.ConclusionsOur results provide evidence that hCAP18/LL-37 contributes to breast cancer metastasis.

Dataset Information

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

Publications

Cathelicidin hCAP18/LL-37 promotes cell proliferation and suppresses antitumor activity of 1,25(OH)<sub>2</sub>D<sub>3</sub> in hepatocellular carcinoma.

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Dataset Information

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

Publications

Cathelicidin hCAP18/LL-37 promotes cell proliferation and suppresses antitumor activity of 1,25(OH)<sub>2</sub>D<sub>3</sub> in hepatocellular carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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