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with RAGE receptor in PCa cells, and blockade of the RAGE/HMGB1 interaction may suppress tumor
[53]
[52]
proliferation . This notion is also validated by our recent works , which revealed that the depletion of
RAGE by siRNA attenuated the proliferation of PCa cells. Our previous study demonstrated that both
RAGE and HMGB1 are co-expressed in PCa specimens, indicating that they may have a cooperative role in
the development of PCa . More recently, Shetty et al. documented that HMGB1 is one of the target pro-
[54]
[31]
inflammatory genes for 18α-glycyrrhetinic acid in PCa cells. Hence, a potential mechanism of HMGB1 in
promoting the multistep process of PCa development may be associated with the activation of
inflammation, and RNAi-based approaches targeting HMGB1/RAGE may act as a novel therapy for PCa.

Most deaths in PCa patients are attributed to the transactivation of AR, which is required for PCa survival
and progression [55,56] . Recent emerging evidence points out that HMGB1 can transactivate the sex steroid
hormone receptors including AR, mineralocorticoid receptor, progesterone receptor, and glucocorticoid
[37]
receptor [57,58] . The transactivation of AR by HMGB1 in PCa may have clinical significance . AR activation
suggests it has an action on endocrine glands responding to androgen stimulation. Moreover, AR activation
is also known to have a crucial role in the progression of androgen-independent PCa . The activation of
[59]
[60]
AR is regulated by various signaling pathways . Thus, these studies indicate that HMGB1 may mediate AR
by either acting as co-activator of AR or binding to RAGE in prostate oncogenesis [Figure 1A].

HMGB1 A POTENTIAL TARGET FOR PCA TREATMENT
HMGB1 is implicated as a late mediator for various human diseases including atherosclerosis, sepsis,
inflammation, and arthritis [16,61-63] . Much evidence shows that HMGB1 can also act as a therapeutic target for
various tumor types including PCa . Furthermore, multiple HMGB1 functions have been identified in
[64]
different types of tumors, including limitless proliferation potential, escape of apoptosis, angiogenesis,
inflammatory microenvironment, and tumor invasion and metastasis. Moreover, HMGB1 has been recently
shown to regulate most of the key cell signaling pathways, including NF-κB, p38, JNK, and p44/42 MAPKs,
which can be triggered by interacting with RAGE and result in cancer progression and metastasis [44,65,66] .
Hence, identification of the potential HMGB1 targeting strategies is of functional significance in inhibiting
the tumorigenesis of PCa.

Antisense and RNA interference (RNAi) techniques are the most used strategies to silence the expression of
[67]
target genes . Gnanasekar et al. demonstrated that silencing of HMGB1 by RNAi significantly
[52]
suppressed cell growth and decreased the number of cells undergoing apoptosis. Furthermore, they also
suggested that targeting RAGE by RNAi inhibited HMGB1-mediated cell proliferation of PCa cells and
[52]
[49]
reduced the secretion of HMGB1 . Moreover, Kang et al. demonstrated that knockdown of RAGE or
suppression of HMGB1 release by RNAi diminished ATP production and decreased tumor growth in vitro
and in vivo. This growth inhibition phenomenon was also demonstrated in androgen-dependent and -
independent PCa in xenograft nude mice. In this case, the RNAi strategies that targeted HMGB1 might be a
desirable approach to reach therapeutic effects against PCa.

Antibody-based treatment is a promising strategy for targeted cancer therapy. For instance, anti-PD1
[68]
antibody treatment has yielded encouraging results in clinical trials . In addition, VEGF mAb therapy
[69]
targeting the angiogenesis process of tumor growth has also been applied . Thus, HMGB1 may be a
promising therapeutic target for PCa, as it is implicated in cell proliferation, apoptosis regulation,
[38]
angiogenesis, and metastases [64,70] . He et al. found that administration of anti-HMGB1 dramatically
suppressed the prostate tumor growth in TRAMP mouse model. The potential inhibition effect of colon
cancer development by anti-HMGB1 has also been reported . More recently, it was revealed that treatment
[71]
with anti-HMGB1 neutralizing antibody prevented angiogenesis in colon cancer . Furthermore, targeting
[72]