Page 112 - Read Online

Melnik et al. J Transl Genet Genom 2022;6:1-45 https://dx.doi.org/10.20517/jtgg.2021.37 Page 15

[504]
Furthermore, p53 is a key inhibitor of AR expression . Milk miR-125b- and miR-30d-mediated
suppression of p53 thus attenuates the activity of crucial negative regulators of androgen and mTORC1
signaling, both related to PCa pathogenesis [Figure 2B] [494,498] .

[448]
Xie et al. demonstrated that porcine MEX miRs reduced the expression of p53 in intestinal epithelial
cells. The expression of p53 is primarily controlled by the interaction of mouse double minute 2 (MDM2)
[505]
and MDM4, which are both negative regulators of p53 expression . MDM4 suppresses p53 transcriptional
activity and facilitates p53 proteasomal degradation via binding MDM2’s E3 ligase activity towards p53 .
[505]
Overexpression of MDM4 has recently been detected in PCa tissue and increases with disease
progression [506-508] . Recent transcriptomic characterization of MEX isolated from cow, donkey, and goat milk
identified MDM4 as a central node protein for all three species, indicating a conserved checkpoint with
higher numbers of interconnections . Notably, MEX-mediated attenuation p53 signaling has been
[509]
implicated to play a role in the pathogenesis of PCa and acne vulgaris .
[494]
Taken together, an interactive network of milk miRs (miR-21, miR-30d, miR-125b, miR148a, and miR-155)
provides an epigenetic regulatory layer that inactivates p53 and activates PI3K-AKT-mTORC1-signaling,
[510]
which drives PCa carcinogenesis . Of note, miR-30d is a critical osteomiR, promoting RUNX2
expression , which is closely linked to RUNX2-mediated bone metastasis in PCa [54,56] .
[511]

MicroRNA-29b
[419]
miR-29b, another prominent miR of commercial cow milk, survives pasteurization and storage . As
[512]
shown in intestinal epithelial cells, bovine MEX miR-29b is taken up by endocytosis . In a dose-dependent
manner, plasma levels of miR-29b increased 6 h after consumption of 0.25, 0.5, and 1.0 L of commercial
milk and affected blood monocyte gene expression . In a synergistic fashion with miR-148a- and miR-21-
[359]
mediated inhibition of DNMT1, miR-29b attenuates DNA methylation via suppression of
DNMT3A/B [513-516] . Thus, milk-derived miRs via attenuation of DNA methylation of developmental genes
[443]
such as INS and IGF1 enhance their expression, resulting in increased mTORC1 activity .

miR-29b suppresses the catabolism of BCAAs via targeting the mRNA for the dihydrolipoamide branched-
chain transacylase (DBT). DBT is the E1α-core subunit of branched-chain α-ketoacid dehydrogenase
(BCKD), which degrades BCAAs . The activity of BCKD is regulated by BCKD kinase, which
[517]
phosphorylates two serine residues in the E1α subunit and thereby inhibits BCKD. Insulin is a known
stimulator of BCKD kinase expression, thereby inhibiting BCKD, which results in increased cellular levels of
BCAAs [518-523] . In synergy with insulin, MEX miR-29b inhibits the oxidative catabolism of BCAAs required
for mTORC1 activation at both the PI3K-AKT-TSC2-RHEB and the BCAA-RAG-Ragulator-RHEB
pathway. Intriguingly, increased expression of PCa EV-associated miR-29b-3p could be detected in PCa
patients compared to controls .
[524]

Of importance, it has been shown in osteoblasts that miR-29b induces protein and mRNA expression of
RUNX2 . Baier et al. demonstrated increased expression of RUNX2 in peripheral blood mononuclear
[359]
[525]
cells of healthy volunteers 6 h after consumption of commercial cow milk. Thus, milk-induced PI3K-AKT
signaling with AKT-mediated nuclear extrusion of FoxO1 as well as MEX miR-29b-induced RUNX2
[53]
expression and enhanced RUNX2 activity provide potential mechanisms for the promotion of PCa bone
[525]
metastasis [54-56,358] .
Milk consumption via upregulation of RUNX2 may not only stimulate skeletal development [459,526,527] and
[359]
linear growth in childhood [261-264] but also promote bone metastasis of PCa [Figure 2B] .
[528]