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Page 2 of 4 Liu et al. Hepatoma Res 2019;5:30 I http://dx.doi.org/10.20517/2394-5079.2019.27

transformation of normal cells. Thus, the HCC development is characterized by an evolutionary process of
mutation-selection-adaptation.

APOBEC3B can generate cytosine-to-uracil (C>U) transversions through deamination. APOBEC3B related
mutation pattern is proved to be widespread in the genome of tumors in many different organs including
[7]
breast, lung, cervix, ovary, bladder, and head and neck . Therefore, APOBEC3B is commonly believed to
be a major force of generating somatic mutations.

[8]
In a recent study, Wang et al. revealed another important role of APOBEC3B in the cancer evolutionary
process of mutation-selection-adaptation. Their study suggests that APOBEC3B can also contribute to
the “selection” and “adaption” of malignant cells via facilitating the immune escape in a deaminase-
independent way. They reported that the elevated abundance of APOBEC3B in HCC predicts a poor
prognosis. Authors demonstrated a high affinity κB site in APOBEC3B promoter and non-canonical NF-
κB signaling pathway up-regulates the expression of APOBEC3B via activating its transcription. With the
animal models of HCC, it was demonstrated that elevated APOBEC3B facilitated the development of HCC
only in the immunocompetent mouse rather than in the immune-deficient mouse. APOBEC3B was proved
+
to recruit TAM, MDSC, and CD8 T cells positive for Programmed cell death ligand 1 through increasing
the secretion of C-C motif chemokine ligand 2 (CCL2). The immunosuppressive effect of APOBEC3B
depends on epigenetic modification. APOBEC3B can inhibit the activity of polycomb repressor complex
2, which is essential for maintaining methylation of H3K27. Therefore, the elevated APOBEC3B in HCC
depresses global H3K27me3 abundance and reduces the occupancy of H3K27me3 on the promoter of
CCL2. Thus, APOBEC3B promotes the immune escape and growth of HCC.

This remarkable study highlights the role of APOBEC3B in regulation of immune microenvironment as a
factor of epigenetic modification. The understanding of APOBEC3B function and the theory of Cancer Evo-
Dev are improved due to their solid evidences. In the meantime, two questions are proposed in this article.
First, in addition to regulating epigenetic modification, APOBEC3B can promote HCC development by
inducing mutation. Second, the role of interaction between HBV and APOBEC3B-mediated inflammatory
microenvironment in HCC evolution should be further investigated. In this study, HBV infection was
not taken into consideration. The immunosuppressive function of APOBEC3B was mainly demonstrated
with the diethylnitrosamine-induced HCC animal model, which can hardly reflect the HBV-induced
carcinogenesis in human. As described in the article, what authors investigated is the “hepatoma-intrinsic
APOBEC3B” rather than APOBEC3B of hepatocytes with chronic inflammation. Therefore, results of this
study cannot represent all the effects of APOBEC3B during HBV-induced hepatocarcinogenesis, especially
its mutagenic function. APOBEC3B contributes the innate immune responses to HBV infection through
[9]
inhibiting the replication of HBV via hyper-editing viral genome . Although APOBEC3B induced HBV
mutations are highly deleterious, a small percentage of viral mutations can facilitate the immune escape or
[5]
the regeneration of hepatocytes .
Interestingly, another recent study revealed the role of APOBEC3B in HCC development from another
aspect, which answers the above questions. It discovered the associations among genetic predispositions,
[10]
inflammation, APOBEC3B, and HBV mutations during the process of HCC development . Interleukin-6
(IL-6) was proved to increase the expression of APOBEC3B and decrease the expression of uracil DNA
glycosylase (UNG), an enzyme essential for DNA repair, thus leading to imbalance of mutagenic forces
and mutation-repairing forces. Two genetic polymorphisms, rs2267401 (G) and rs3890995 (C), were proved
to intensify the IL-6 induced APOBEC3B-UNG imbalance through affecting the activities of APOBEC3B
promoter and UNG enhancer, respectively. These two genetic polymorphisms were also proved to be
significantly associated with increased HCC risk by using a large case-control study involving 5221
participants. Besides, variant genotypes at rs2267401 were also demonstrated to improve the accumulation