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Table 2. Target genes of miR-21 related to the pathogenesis and progression of PCa
miR-21 targets Regulatory proteins Ref.
PTEN Phosphatase and tensin homolog [71]
PDCD4 Programmed cell death 4 [72]
FOXO1A Forkhead box transcription factor O1a [73,74]
KLF5 Kruppel-like factor 5 [87]
IGFBP3 IGF binding protein 3 [88]
CDKN1C Cyclin-dependent kinase inhibitor 1C [89]
MARCKS Myristoylated alanine-rich protein kinase C substrate [90]
TGFBR2 Transforming growth factor β-receptor II [91]
FBXO11 F-box only protein 11 [92]
RECK Reversion-inducing cysteine-rich protein with KAZAL motifs [93]

protein 1 (PIK3IP1) . PIK3IP1 directly binds to the p110 catalytic subunit of PI3K and downregulates
[100]
[102]
PI3K activity . PIK3IP1 negatively regulates PI3K activity and thereby suppresses activation of AKT .
[102]
miR-148a-mediated suppression of PIK3IP1 thus enhances PI3K-AKT-mTORC1 signaling. It has recently
been demonstrated that the E2F transcription factor 1 (E2F1)/DNA methyltransferase 1 (DNMT1)
[103]
inhibitory axis of AR transcription is activated during the emergence of CRPC . It has been shown that
miR-148a-mediated suppression of DNMT1 induces the expression of apoptotic genes in hormone-
[104]
[105]
refractory PCa cells . In contrast, Lee et al. provided evidence that reduced expression of DNMT1 was
associated with EMT induction and cancer stem cell phenotype, enhancing tumorigenesis and metastasis of
PCa. In a synergistic fashion with miR-21, miR-148a suppresses the expression of PTEN and
DNMT1 [98,106-110] . miR-21- and miR-148a-mediated suppression of DNMT1 with consecutive promoter gene
demethylation increases the expression of insulin (INS) , IGF-1 (IGF1) [112,113] , and mechanistic target of
[111]
rapamycin (TOR) . These are developmental genes of the insulin/IGF-1/PI3K/AKT/mTORC1 signaling
[114]
cascade, which is upregulated in PCa. Collectively, there is compelling evidence that both miR-21 and miR-
148a modify epigenetic regulation of PCa, enhancing PI3K-AKT-mTORC1 signal transduction.

MILK-INDUCED PI3K-AKT-MTORC1 SIGNALING
Calcium
Earlier studies suspected dairy calcium as a promoter of PCa pathogenesis . The milk calcium content
[115]
differs between cattle breeds, exhibiting the lowest calcium content in Holstein-Friesian (1275.0 ±
1.5 mg/kg) and the highest in Jersey cows (1449.2 ± 7.8 mg/kg) . It has been suggested that high calcium
[116]
intake may lower levels of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], which may protect against
PCa . The Physicians’ Health Study, a cohort of male US physicians, compared men consuming ≤ 150 mg
[117]
calcium/day from dairy products with men consuming > 600 mg/day. Higher calcium intake was associated
with a 32% higher risk of PCa . Other studies concluded that men with the highest intake of dairy
[117]
products and calcium were more likely to develop PCa than men with the lowest intake [118,119] . In contrast,
Hayes et al. and Berndt et al. found no significant association between calcium intake and PCa risk.
[121]
[120]
According to a systematic review and meta-analysis of cohort studies, total calcium and dairy calcium
intakes, but not non-dairy calcium or supplemental calcium intakes, were positively associated with total
PCa risk . Thus, dietary calcium co-uptake with milk consumption does not exclusively explain milk’s
[122]
impact on prostate carcinogenesis. Although direct experimental evidence is lacking that milk-derived
calcium increases intracellular calcium levels and promotes calcium-mediated proliferative signaling in PCa
[123]
cells, recent translational evidence may link dietary calcium intake and PCa development . Although
intracellular calcium has been suggested to promote PI3K-AKT signaling and PCa development , plasma
[124]
calcium levels are physiologically maintained within close limits that should not modify calcium