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Table 1. Frequency of common genetic alterations in the PI3K-AKT-mTORC1 pathway in PCa
Altered genes Frequency in PCa (%)
PTEN deletion/mutation 16.4-32.0
DEPTOR amplification 5.1-21.4
SGK mutation/amplification 5.6-20.5 (SGK3)
0.2-2.7 (SGK1)
FOXO deletion 0-15.2 (FOXO1)
4.5-13.4 (FOXO3)
MAP3K7 deletion 5.9-14.8
RRAGD deletion 6.5-14.4
SESN1 mutation/deletion 5.4-13.6
PIK3CA mutation/amplification 5.5-11.5
PIK3C2B mutation/amplification 1.4-11.5
PDPK1 amplification 0-8.1

[22] [39]
Data provided by Shorning et al. and Armenia et al. .
Epigenetic upregulation of PI3K-AKT-mTORC1 in PCa
Not only genetic but also epigenetic deviations contribute to PCa tumorigenesis and disease progression.
Epigenetic alterations change DNA methylation, histone modifications, and the pattern of microRNA (miR)
expression [63-68] .

MicroRNA-21 in PCa
miR-21 is regarded as a critical oncomiR contributing to PCa carcinogenesis and progression [69,70] . miR-21
targets the mRNAs of key tumor suppressor genes including PTEN , programmed cell death 4
[71]
[75]
[72]
(PDCD4) , and forkhead box O1A [73,74] . Of note, FoxO3a, which is deregulated in PCa , inhibits the
expression of miR-21 . In contrast, androgens enhance the expression of miR-21, and AR-regulated miR-
[76]
[77]
21 promotes hormone-dependent and -independent PCa growth . miR-21 and miR-375 of urinary
exosomes have recently been reported to serve as biomarkers for the detection and prognosis of PCa [78,79] . In
accordance, urine miR-21-5p is regarded as a potential non-invasive biomarker in patients with PCa [80,81] .
Thus, upregulated miR-21 and miR-30c in serum/plasma emerged as biomarkers of PCa , as well as
[82]
increased expression of miR-21 in peripheral blood mononuclear cells . Furthermore, miR-21 is
[83]
significantly upregulated in PCa compared to benign prostatic hyperplasia [84,85] . The expression of miR-21
and WNT-11 are associated with high Gleason scores in PCa tissues, promoting epithelial-mesenchymal
[86]
transition (EMT) in aggressive PCa cells . Further target genes of miR-21 are presented in Table 2.
Thus, there is compelling evidence that miR-21 including circulating miR-21, which is elevated in the serum
and exosomes of PCa patients, plays an important role in PCa carcinogenesis, progression, and
metastasis [75-95] .

MicroRNA-148a in PCa
miR-148a is another oncogenic miR that plays a pivotal role in PCa [96-99] . Increased levels of miR-148a-3p in
serum are associated with PCa . miR-148a-3p expression is increased in PCa tissue and exhibits higher
[96]
[97]
expression levels correlating with increased Gleason score . miR-148a is an AR-responsive miR promoting
LNCaP prostate cell growth by repressing its target cullin-associated neddylation-dissociated protein 1 . A
[99]
significant growth advantage for LNCaP cells transfected with pre-miR-148a was found with significantly
increased numbers of cells in the S phase . miR-148a silences cyclin-dependent kinase inhibitor 1B. miR-
[100]
148a transfection into LNCaP cells increased S-phase transition and enhanced cell proliferation . Further
[101]
target genes of miR-148a are B-cell translocation gene 2 and phosphatidylinositol 3-kinase-interacting