Milk lactoperoxidase decreases ID1 and ID3 expression in human oral squamous cell carcinoma cell lines

Panahipour, Layla; Biasi, Maria De; Bokor, Theresa Sophia; Thajer, Alexandra; Haiden, Nadja; Gruber, Reinhard

doi:10.1038/s41598-020-62390-4

Cited by 4 publications

(18 citation statements)

References 47 publications

(53 reference statements)

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“…PDGF-BB and bFGF are strong mitogens for mesenchymal cells [ 34 ], thus in line with the increased Ki-67 staining [ 34 ] and cyclinD1 expression [ 35 ]. Also, in line with our previous data is that aqueous fraction of micellar casein and whey powder decrease the ID1 and ID3 genes in HSC2 cells presumably via lactoperoxidase activity [ 14 ]. The present study is thus another piece of evidence that processing of milk into casein and whey powder maintains the TGF-β and presumably also the lactoperoxidase activity.…”

Section: Discussionsupporting

confidence: 91%

“…The latter is an indirect evidence for the presence of lactoperoxidase, a heat stable milk enzyme, in casein and whey powder. We thus show that casein and whey maintain the basic in vitro properties of pasteurized milk we have recently reported [ 11 , 12 , 14 ].…”

Section: Discussionsupporting

confidence: 68%

“…The TGF-β activity is not related to changes of the proliferation marker protein Ki-67 and cyclinD1 expression in gingival fibroblasts. Moreover, we provide data that aqueous fraction of micellar casein and whey powder exert the same activity as pasteurized milk in the oral squamous epithelial cell line HSC2 by decreasing the ID1 and ID3 genes [ 14 ]. The latter is an indirect evidence for the presence of lactoperoxidase, a heat stable milk enzyme, in casein and whey powder.…”

Section: Discussionmentioning

confidence: 99%

“…Among the bioactive proteins in milk is also lactoperoxidase with its application in food, cosmetics and medical industries as it exhibits an antimicrobial activity [ 13 ]. Lactoperoxidase provokes cellular responses, for example to decrease the expression of DNA-binding protein inhibitor 1 (ID1) and ID3 in HSC2 human oral squamous carcinoma cells [ 14 ]. IDs proteins are helix–loop–helix transcription factors regulating cell-cycle progression and cell differentiation [ 15 ], also during wound healing [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Considering that regular infant formula holds a potent TGF-β activity [ 12 ] that reduces allergic reactions in ovalbumin-tolerized mice [ 3 ], it is likely that this is also true for the main ingredient’s casein and whey protein. If, however, casein and whey, similar to milk [ 14 ], activate cells of the epithelial cell lineage remains to be studied. The aim of the present study was therefore to investigate casein and whey powder with respect to provoking a TGF-β response in gingival fibroblasts and decreasing ID1 and ID3 expression in HSC2 oral squamous carcinoma cells.…”

Section: Introductionmentioning

confidence: 99%

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Micellar Casein and Whey Powder Hold a TGF-β Activity and Regulate ID Genes In Vitro

et al. 2021

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Casein and whey being food supplements have been considered to be used in oral health care products. However, the response of oral cells to micellar casein and whey powder remains unclear. Considering that milk contains the growth factor TGF-β, and lactoperoxidase was recently reported to decrease the expression of inhibitor of DNA-binding (ID) proteins, there is a rationale to assume that casein and whey can also provoke these responses in oral cells. To examine the TGF-β activity, gingival fibroblasts were exposed to reconstituted casein and whey powder from food supplement before the expression of TGF-β target genes were analyzed by reverse transcription-quantitative polymerase chain reaction. Immunoassays were performed for interleukin11 (IL11) in the cell culture supernatant and for TGF-β in the reconstituted casein and whey. We blocked TGF-β by neutralizing the antibody and the TGF-β receptor type I kinase with the inhibitor SB431542. We also showed smad3 phosphorylation and smad2/3 nuclear translocation by Western blot and immunostaining, respectively. Moreover, with reconstituted casein and whey powder, ID1 and ID3 expression analysis was evaluated in HSC2 human oral squamous carcinoma cells. We report here that casein and whey powder caused a robust increase of TGF-β target genes interleukin11 (IL11), NADPH oxidase 4 (NOX4) and proteoglycan4 (PRG4) in gingival fibroblasts that was blocked by SB431542 and the neutralizing antibody. Moreover, casein and whey powder increased the phosphorylation of smad3 and nuclear translocation of smad2/3. No changes of proliferation markers Ki67 and cyclinD1 were observed. Furthermore, reconstituted casein and whey powder decreased ID1 and ID3 expression in the HSC2 oral squamous carcinoma cells. These findings suggest that the processing of milk into casein and whey powder maintains the TGF-β activity and its capacity to regulate ID1 and ID3 genes in oral fibroblasts and oral squamous carcinoma cells, respectively. These data increase the scientific knowledge on the biological activity of casein and whey with a special emphasis on oral health.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Micellar Casein and Whey Powder Hold a TGF-β Activity and Regulate ID Genes In Vitro

et al. 2021

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RNAseq of TGF-β receptor type I kinase-dependent genes in oral fibroblast exposed to milk

et al. 2021

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Background Milk is a rich source of natural growth factors that may support oral tissue homeostasis and wound healing. We had shown earlier that blocking TGF-β receptor type I kinase with the inhibitor SB431542 abolished the expression of IL11 and other genes in human gingival fibroblasts exposed to the aqueous fraction of milk. Our aim was to identify the entire signature of TGF-β receptor type I kinase-dependent genes regulated by the aqueous fraction of human milk. Result RNAseq revealed 99 genes being strongly regulated by milk requiring activation of the SB431542-dependent TGF-β receptor type I kinase. Among the SB431542-dependent genes is IL11 but also cadherins, claudins, collagens, potassium channels, keratins, solute carrier family proteins, transcription factors, transmembrane proteins, tumor necrosis factor ligand superfamily members, and tetraspanin family members. When focusing on our candidate gene, we could identify D609 to suppress IL11 expression, independent of phospholipase C, sphinosine-1 phosphate synthesis, and Smad-3 phosphorylation and its nuclear translocation. In contrast, genistein and blocking phosphoinositide 3-kinases by wortmannin and LY294002 increased the milk-induced IL11 expression in gingival fibroblasts. Conclusion Taken together, our data revealed TGF-β receptor type I kinase signaling to cause major changes of the genetic signature of gingival fibroblasts exposed to aqueous fraction of human milk.

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Milk-Derived Proteins and Peptides in Head and Neck Carcinoma Treatment

Wang

Liu

et al. 2022

Biomolecules

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Research investigating milk-derived proteins has brought to light the potential for their use as novel anticancer agents. This paper aims to systematically review studies examining the effectiveness of milk-derived proteins in the treatment of head and neck cancer. A systematic literature search of Medline, Evidence-Based Medicine, and Web of Science databases including papers published from all dates was completed. Inter-rater reliability was high during the title, abstract, and full-text screening phases. Inclusion criteria, exclusion criteria, and data extraction were based on the PICOS tool and research questions. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-Analysis criteria. Eligible in vitro and in vivo studies (n = 8/658) evaluated lactoferrin, α-lactalbumin, and its complexes, such as HAMLET, BAMLET and lactalbumin-oleic acid complexes, as well as lactoperoxidase, whey, and casein. Their effectiveness in the treatment of head and neck cancer cells lines found that these compounds can inhibit tumour growth modulate cancer gene expression, and have cytotoxic effects on cancer cells. However, the exact mechanisms by which these effects are achieved are not well understood. Systematically designed, large, optimally controlled, collaborative studies, both in vitro and in vivo, will be required to gain a better understanding of their potential role in the treatment of head and neck cancer.

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Milk lactoperoxidase decreases ID1 and ID3 expression in human oral squamous cell carcinoma cell lines

Cited by 4 publications

References 47 publications

Micellar Casein and Whey Powder Hold a TGF-β Activity and Regulate ID Genes In Vitro

Micellar Casein and Whey Powder Hold a TGF-β Activity and Regulate ID Genes In Vitro

RNAseq of TGF-β receptor type I kinase-dependent genes in oral fibroblast exposed to milk

Milk-Derived Proteins and Peptides in Head and Neck Carcinoma Treatment

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