BCL2 role in the prostate cancer progression has not been clarified
completely. There are also reports that imply association between
PGR and BCL2 overexpression and aggressive phenotypes of pros-
tate cancer [99–102]. It is clear from the integrative co-expression
network of primary tumor that there is a positive correlation
between PGR and BCL2. Regulation of BCL2 through direct
binding of PGR has also been reported previously [102, 103]. Tak-
ing advantage of the miRNA regulatory interactions in the integra-
tive co-expression networks, we can track the effects of miRNAs on
these key regulatory signatures. In the integrative co-expression
network for primary tumor PGR and its downstream target, PGR
and BCL2 are targeted by multiple overexpressed miRNAs (miR-
20a,miR-32,miR-135aandmiR-629forHOXD10,miR-19a,
miR-19b and miR-375 for IGFBP3, miR-25, miR-375 and
miR-548c-3p for BCL2, and miR-19a andmiR-19b for PGR),
these inhibitory regulations might be an important reason for the
downregulation of the mentioned genes in the primary prostate
tumor.
STAT3, JUN, and JUNB are three key signatures that have
been identified in the metastatic prostate cancer integrative net-
work. STAT3 is a member of STAT (Signal Transducers and Acti-
vators of Transcription) family. It acts in response to cytokines and
growth factors, particularly IL6 [104]. STAT3 overexpression has
been observed in prostate cancer and based on this finding, inacti-
vation of STAT3/IL6 was examined for prostate cancer treatment;
however, this inhibition resulted in the progress of prostate cancer
to metastatic phase [86, 105]. Despite the indispensable role of
STAT3 and IL6 in prostate cancer, their role in prostate cancer
progression must be stage and condition dependent. IL6ST and
IRF1 that are present in the metastatic state integrative
co-expression network are STAT3 important regulators
[106]. Based on the network analysis, their downregulation may
have an important effect on the STAT3 inhibition. The integrative
co-expression network also introduces five overexpressed miRNAs
(miR-671-5p,miR-665,miR-663,miR 512-3p,andmiR-371-5p)
which suppress STAT3 expression. The synergistic inhibitory effect
of these mentioned factors has a substantial effect on suppression of
STAT3 in metastatic prostate cancer.
JUN and JUNB are other key molecular signatures in the
metastatic state integrative co-expression network. These genes
are members of the AP1 transcription factor family [107]. There
are other members of the AP1 transcription factor family in the
network as well (FOS,FOSB,andATF3) which are downregulated.
These genes are the mediators of TGFβsignaling pathway and its
misfunction leads to progressive phenotypes of prostate cancer
[108, 109]. Downregulation of AP1 transcription factors is an
important factor for TGFβsignaling pathway aberration in meta-
static prostate cancer based on our integrative co-expression268 Faiz M. Khan et al.