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Lv. J Transl Genet Genom 2021;5:414-22 https://dx.doi.org/10.20517/jtgg.2021.34 Page 416

Although the upregulation of HMGB1 has been found in several cancers, its role in PCa remains elusive. In
addition, our previous study revealed that both HMGB1 and RAGE are highly expressed in PCa tissues and
[31]
serve as predictive factors for the poor prognosis of PCa patients . Moreover, we also clarified that the
HMGB1/BRG1 interaction was associated with the activation of Akt function, resulting in proliferation and
metastasis of PCa . These results suggest that HMGB1 might be a new prognostic biomarker and
[32]
therapeutic target for PCa. Here, we summarize the recently published literature to highlight and speculate
on the interactions of HMGB1 and RAGE in PCa progression and the possible strategies for the targeted
therapy of PCa.

HMGB1 AND RAGE IN THE PROGNOSTIC PREDICTION OF PCA
HMGB1 is reported to be frequently increased in various types of cancer [33-35] . Similarly, HMGB1 is also
identified to be upregulated in PCa [31,36] . Intriguingly, androgen deprivation caused the secretion of HMGB1
[37]
in prostatic stromal cells, which was considered to be correlated with metastatic PCa . These results
support the notion that hormone resistance or metastasis of PCa may be due to androgen deprivation
[38]
therapy, ultimately increasing the level of HMGB1. Furthermore, He et al. showed in the transgenic
adenocarcinoma mouse prostate (TRAMP) model that HMGB1 facilitates the invasion of cancer, and
HMGB1 released in serum during cancer progression is associated with severity of clinical pathology.

[36]
Overexpression of RAGE and HMGB1 has been observed in PCa. Ishiguro et al. found that the mRNA
expression of HMGB1 and its cognate receptor, RAGE, is remarkably higher in primary PCa tissues and
[37]
hormone-refractory tissues than normal prostate tissues. Kuniyasu et al. described that amphoterin is the
major product of the HMGB1 gene co-expression with RAGE and functions as a promoting factor in
metastatic PCa. Further, Li et al. explored the relationship of HMGB1 expression with the
[39]
clinicopathological parameters and overall survival of PCa. They also showed that HMGB1 expression is
associated with clinical stage (pT), Gleason grade, PSA level, biochemical recurrence, and poor overall
survival. Moreover, they revealed that three PCa cells (PC-3, DU145, and LNCaP) had upregulated HMGB1
mRNA and protein compared to non-transformed immortalized prostate cell RWPE-1. Likewise, our
previously study highlights and adds to the theme of HMGB1 acting as a biomarker for advanced stages and
poor prognosis for PCa [31,32] . All these preclinical and clinical studies greatly exhibited that HMGB1 may
play a crucial role in the progression of PCa. In addition, research in other laboratories has also shown that
members of HMGB1 are consistently increased in different types of human malignancies, including renal
[40]
[33]
cell carcinoma , bladder cancer , hepatocellular carcinoma , gastric cancer , colorectal cancer , breast
[42]
[41]
[19]
[43]
[44]
cancer , and lung cancer . Thus, it would be interesting to survey tumor samples to further examine the
incidence of the abnormal expression of HMGB1 and RAGE in other types of tumors. This systematic
analysis would be helpful to determine whether HMGB1 can serve as a reliable biomarker for prostate or
other type of cancers.
HMGB1 AND RAGE INTERACTING IN PCA
Growing evidence shows that chronic inflammation is one of the etiological factors of PCa [45-48] . The
HMGB1/RAGE inflammatory pathway promotes growth of tumor cells . The interactions of HMGB1 and
[49]
RAGE have been implicated in various types of cancer including PCa . Zhou et al. showed that the
[30]
[30]
HMGB1/TLR-4/RAGE pathway promotes cell survival via sCLU induction in human prostate tumor cells.
However, the specific roles of HMGB1 in PCa are related to its different locations. It has been reported that
extracellular HMGB1 has an entirely different role, functioning as one of the damage-associated molecular
patterns or alarmin to activate the innate immune system either alone or in conjunction with cytokines or
[50]
bound DNA . In the extracellular environment, RAGE binds a downstream domain of HMGB1 at residues
150-183, which regulates chemotaxis, growth, and differentiation in epithelial cells . HMGB1 combines
[51]