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Page 14 Melnik et al. J Transl Genet Genom 2022;6:1-45 https://dx.doi.org/10.20517/jtgg.2021.37

[458]
miR-21-5p-mediated suppression of SMAD7 increases the expression of RUNX2 , a key transcription
[459]
factor promoting bone formation . In fact, it has been demonstrated that exosomal hsa-miR-21-5p
[460]
derived from GH-secreting pituitary adenoma promotes abnormal bone formation in acromegaly . In
human PCa (PC-3U) cells, physical association of SMAD7 and β-catenin was found to be important for
TGF-β-induced apoptosis . Notably, increased expression of RUNX2 has been observed in PCa [54,358] and
[461]
breast cancer-mediated bone metastasis [462,463] .

MicroRNA-148a
miR-148a represents the most abundant miR in cow milk, milk fat, EVs, and MEX [418,436,451,464-467] . miR-148a is
highly conserved among mammals [418,468] and has been identified as a domestication gene of dairy cows,
enhancing milk yield [469,470] . Human and bovine milk miR-148a nucleotide sequences are identical [418,468,471,472] .
Milk-derived bovine miR-148a is thus able to affect gene expression of human milk consumers (cross-
species communication) . DNMT1 is a major target of miR-148a [109,110] , which explains MEX-mediated
[473]
suppression of DNMT1 expression [418,438] , a pivotal postnatal mechanism modifying epigenetic regulation
activating mTORC1 signaling [153,439,443,474] . In fact, DNMT1 inhibition upregulates the expression of the
[475]
transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) , which promotes the expression of
mTOR (MTOR) . By targeting the catalytic subunit α1 of AMPK (PRKAA1) as well as the AMPK
[476]
regulatory subunit γ2 (PRKAG2), miR-148a attenuates the expression AMPK [477,478] . AMPK-mediated
phosphorylation of TSC2 and Raptor suppresses mTORC1 activity [315,479] . Importantly, miR-148a inhibits
PTEN, the upstream negative regulator of PI3K [106-108] , which is downregulated in PCa [22,39] . In addition, miR-
[102]
148a targets PIK3IP1, the direct negative regulator of PI3K . Thus, milk miR-148a epigenetically augments
several checkpoints activating mTORC1 [Figure 2B].

MicroRNA-155 and microRNA-223
miR-155 and miR-223 are dominant immune regulatory miRs of bovine milk [427,428,466,480,481] . miR-155 targets
[483]
[482]
IGFBP3 . In synergy with miR-148a, miR-155 also suppresses the expression of PTEN . Both miR-155
and miR-223 suppress the proteasomal degradation mTOR via targeting F-box and WD40 domain protein 7
(FBXW7) [484,485] , a critical regulatory checkpoint involved in ubiquitination-dependent degradation of
mTOR . Moreover, FBXW7-mediated mTOR degradation cooperates with PTEN in tumor
[486]
suppression . In addition, FBXW7 promotes the degradation of cyclin E, c-MYC, MCL-1, JUN, NOTCH,
[486]
and aurora kinase A (AURKA) . In primary PCa, decreased expression of FBXW7 mRNA compared to
[487]
normal prostate tissues has been detected . Significant overexpression and gene amplification of AURKA
[488]
[489]
and n-MYC have been detected in 40% of neuroendocrine PCa and 5% of PCa, respectively .
MicroRNA-125b and microRNA-30d
miR-125b, another abundant miR component of cow milk, resists gastrointestinal digestion [428,465,481] . miR-
30d belongs to the top 10 expressed milk miRs when comparing the sequence data of various species
including Bos taurus and Homo sapiens [418,436,490,491] . After oral gavage of bovine MEX transfected with
fluorophore (IRDye)-labeled miR-30d as well as miR-21 to C57BL/6 mice, these miRs accumulated in
murine placenta and embryos . Of note, miR-125b and miR-30d are key inhibitors of TP53, the guardian
[437]
of the genome [492-494] . In fact, increased expression of miR-125b enhances PCa growth and attenuates the
[495]
expression of p14(ARF), modifying p53-dependent and -independent apoptosis in PCa . Loss of p53
[496]
[497]
function plays a critical role in prostate carcinogenesis, especially in early stage . Bovine MEX miR-125b
and miR-30d via targeting TP53 may represent another mechanistic link of milk signaling, enhancing
[498]
mTORC1 in PCa . Notably, p53 induces the expression of a group of p53 target genes in the IGF-
1/AKT/mTORC1 pathway. These gene products are negative regulators of the IGF-1/AKT/mTORC1
[500]
[498]
pathway in response to stress signals . They are IGFBP3 , PTEN [500-503] , TSC2 , and AMPK β1 .
[500]
[499]