Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts

LL-37, the active product of human cathelicidin antimicrobial peptide (CAMP) has a broad spectrum of antibacterial activity. LL-37 also has important physiological functions in immune regulation, angiogenesis and in modulating apoptosis. The roles of LL-37 in oral squamous cell carcinoma (OSCC) are still not clear. The correlation between DNA methylation and human CAMP expression is also unknown. Here human CAMP/LL-37 expression was assessed by immunohistochemistry in normal and OSCC tissues. The results indicated that low expression of CAMP/LL-37 correlated with histological differentiation and lymph node metastasis and also promoted tumor progression. A cell-specific methylation pattern in the promoter region of human CAMP was detected. Treatment with 5-aza-2′-deoxycytidine, a DNA demethylation reagent can increase human CAMP expression in epithelial cancer cells. The reporter assay showed that unmethylated human CAMP promoter activity was significantly higher than methylated promoter activity. Taken together, these results suggested that human CAMP/LL-37 might act as a tumor-suppressor in OSCC and DNA methylation might play roles during carcinogenesis via directly downregulating human CAMP promoter activity.

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“…Meanwhile, tumor-promoting effects have also been described [3, 6, 7]. The role of LL-37 in tumor development is tissue specific [6].…”

Section: Discussionmentioning

confidence: 99%

DNA methylation directly downregulates human cathelicidin antimicrobial peptide gene (CAMP) promoter activity

Chen

Qin

et al. 2017

Oncotarget

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“…Additionally, at the cytoskeletal level, it was observed that cathelicidin preferentially affected tumoral vimentin, but not mouse host fibroblast vimentin. In view of the fact that vimentin production in tumor stroma is linked with short survival time of patients suffering from colon cancer, targeted treatment with cathelicidin appears to be a promising direction (Cheng et al 2014 ).…”

Section: Colon Cancermentioning

confidence: 99%

The Role of Cathelicidin LL-37 in Cancer Development

Piktel

Niemirowicz

Wnorowska

et al. 2015

Arch. Immunol. Ther. Exp.

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LL-37 is a C-terminal peptide proteolytically released from 18 kDa human cathelicidin protein (hCAP18). Chronic infections, inflammation, tissue injury and tissue regeneration are all linked with neoplastic growth, and involve LL-37 antibacterial and immunomodulatory functions. Such a link points to the possible involvement of LL-37 peptide in carcinogenesis. An increasing amount of evidence suggests that LL-37 can have two different and contradictory effects—promotion or inhibition of tumor growth. The mechanisms are tissue-specific, complex, and depend mostly on the ability of LL-37 to act as a ligand for different membrane receptors whose expression varies on different cancer cells. Overexpression of LL-37 was found to promote development and progression of ovarian, lung and breast cancers, and to suppress tumorigenesis in colon and gastric cancer. This review explores and summarizes the current views on how LL-37 contributes to immunity, pathophysiology and cell signaling involved in malignant tumor growth.

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“…To determine such an effect of ITFs, we measured in ITF-treated animals, the mRNA expression of major structural proteins such as TJ, occludin and ZO-1, as well as AMPs DEFB1 and CRAMP. All these molecules are involved in the physical and chemical barriers of the mucosa ( 32 , 33 ). The RT-qPCR analysis showed that ITF IV but not ITF I supplementation prevented caerulein-induced downregulation of occludin and ZO-1 as well as the downregulation of DEFB1 and CRAMP (Figures 2 A–D).…”

Section: Resultsmentioning

confidence: 99%

Inulin-Type Fructans Modulates Pancreatic–Gut Innate Immune Responses and Gut Barrier Integrity during Experimental Acute Pancreatitis in a Chain Length-Dependent Manner

et al. 2017

Front. Immunol.

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Acute pancreatitis (AP) is a common abdominal inflammatory disorder and one of the leading causes of hospital admission for gastrointestinal disorders. No specific pharmacological or nutritional therapy is available but highly needed. Inulin-type fructans (ITFs) are capable of modifying gut immune and barrier homeostasis in a chemistry-dependent manner and hence potentially applicable for managing AP, but their efficacy in AP has not been demonstrated yet. The current study aimed to examine and compare modulatory effects of ITFs with different degrees of fermentability on pancreatic–gut immunity and barrier function during experimentally induced AP in mice. BALB/c mice were fed short (I)- or long (IV)-chain ITFs supplemented diets for up to 3 days before AP induction by caerulein. Attenuating effects on AP development were stronger with ITF IV than with ITF I. We found that long-chain ITF IV attenuated the severity of AP, as evidenced by reduced serum amylase levels, lipase levels, pancreatic myeloperoxidase activity, pancreatic edema, and histological examination demonstrating reduced pancreatic damage. Short-chain ITF I demonstrated only partial protective effects. Both ITF IV and ITF I modulated AP-associated systemic cytokine levels. ITF IV but not ITF I restored AP-associated intestinal barrier dysfunction by upregulating colonic tight junction modulatory proteins, antimicrobial peptides, and improved general colonic histology. Additionally, differential modulatory effects of ITF IV and ITF I were observed on pancreatic and gut immunity: ITF IV supplementation prevented innate immune cell infiltration in the pancreas and colon and tissue cytokine production. Similar effects were only observed in the gut with ITF I and not in the pancreas. Lastly, ITF IV but not ITF I downregulated AP-triggered upregulation of IL-1 receptor-associated kinase 4 (IRAK-4) and phosphor-c-Jun N-terminal kinase (p-JNK), and a net decrease of phosphor-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 (p-NF-κB p65) nuclear translocation and activation in the pancreas. Our findings demonstrate a clear chain length-dependent effect of inulin on AP. The attenuating effects are caused by modulating effects of long-chain inulin on the pancreatic–gut immunity via the pancreatic IRAK-4/p-JNK/p-NF-κBp65 signaling pathway and on prevention of disruption of the gut barrier.

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Cathelicidin suppresses colon cancer development by inhibition of cancer associated fibroblasts

Cited by 27 publications

References 39 publications

DNA methylation directly downregulates human cathelicidin antimicrobial peptide gene (CAMP) promoter activity

DNA methylation directly downregulates human cathelicidin antimicrobial peptide gene (CAMP) promoter activity

The Role of Cathelicidin LL-37 in Cancer Development

Inulin-Type Fructans Modulates Pancreatic–Gut Innate Immune Responses and Gut Barrier Integrity during Experimental Acute Pancreatitis in a Chain Length-Dependent Manner

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