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
Key Findings
- LL‑37 overexpression speeds up liver cancer cell proliferation and tumor growth in mice
- LL‑37 activates the EGFR/HER2‑PI3K/Akt pathway, driving cancer cell growth
- Vitamin D (1,25‑OH2D3) increases LL‑37 levels, and higher LL‑37 weakens vitamin D’s anti‑tumor activity
Practical Outcomes
- For self‑experimenters, this suggests that boosting LL‑37 (e.g., via certain supplements or immune‑stimulating practices) could be risky if you have liver issues, and that high vitamin D doses might paradoxically raise LL‑37 and blunt its anti‑cancer benefits. No specific dosing changes are recommended, but monitoring liver health and being cautious with interventions that raise LL‑37 is prudent.
Summary
The peptide LL‑37, which helps fight infections, was found to make liver cancer cells grow faster and to block the anti‑cancer effects of vitamin D in lab dishes and mouse tumors. It does this by turning on the EGFR/HER2‑Akt signaling pathway. Vitamin D itself raises LL‑37 levels, which could unintentionally reduce vitamin D’s own tumor‑fighting power in liver cancer.
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<sup>LL-37</sup> xenograft tumor. Interestingly, even though the expression of hCAP18/LL-37 was significantly downregulated in HCC cells and tumors, 1,25(OH)<sub>2</sub>D<sub>3</sub> treatment significantly upregulated the hCAP18/LL-37 level both in HCC cells and xenograft tumors. Moreover, 1,25(OH)<sub>2</sub>D<sub>3</sub> together with si-LL-37 significantly enhanced the antitumor activity of 1,25(OH)<sub>2</sub>D<sub>3</sub> 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)<sub>2</sub>D<sub>3</sub> 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)<sub>2</sub>D<sub>3</sub> supplementation therapy in HCC.
Study Information
pubmed
2022
2022-01-17T00:00:00.000Z
10.1038/s41420-022-00816-w
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