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Cao Cancer Evo-Dev

termed as “signature”. The APOBECs-related mutation may cooperate with both oxidative stress metabolism
signature is widely prevalent in more than half of all and Ras/MAPK pathways in hepatocarcinogenesis [113] .
cancer types under investigations, suggesting that the ActivatedSTAT3/IL-6 and NF-κB/TNF-α can induce
inflammatory response is the common mechanism hepatocytes to lose their epithelial characteristics (EMT)
by which mutations are generated. Even though, the and initiate backward evolution. TGF-β1 can facilitate
frequencies of somatic mutations in a single gene are EMT, which can be enhanced by IL-6 and TNF-α. The
not high in the patient population. For example, the synergistic effect of those three cytokines can promote
rates of mutation in the cording regions of ARID1A and the transformation of normal hepatocytes into stem-like
ARID2, two genes with classic HCC-related genetic cells. Antiviral therapy can significantly reduce the risks
variations, are 16.8% and 5.6% respectively [111] . Such a of occurrence and postoperative recurrence by HCC via
low detection rate of each mutation makes it unable to relieving hepatic inflammation [50-53,119] , possibly because
be applied for the prediction, prevention, early diagnosis, termination of inflammation can destroy the fertile
and treatment of cancers. However, somatic mutations in environment for cancer evolution.
different genes with a similar function can alter a specific
signal pathway that is related to the stem characteristic of AID/APOBECs-regulated demethylation
cancers and therefore promote carcinogenesis. For the and EMT are important in malignant
most malignancies, so-called driver somatic mutations, transformation
mostly at low frequencies in tumor tissues, alter a limited AID/APOBECs not only promote somatic hypermutation
number of cellular signaling pathways through which but also regulate gene expression epigenetically
a growth advantage can be incurred. All of the known by directly deaminating 5-methylcytosine (5mC) or
driver genes can be classified into one or more of 12 5-hydroxymethylcytosine (5hmC) in concert with
pathways of three major functions: cell survival, cell fate, base-excision repair to exchange cytosine, thus
and genome maintenance. Cell survival contains “cell promoting gene demethylation and removing epigenetic
cycle/apoptosis”, “RAS”, “phosphoinositide 3-kinase memory to stabilize the pluripotent state in embryonic
(PI3K)”, “STAT”, “mitogen-activated protein kinase stem cells [120,121] . EMT, a driving force behind the
(MAPK)”, and “transforming growth factor β (TGF-β)”. development of cancers, in its various forms is driven
“NOTCH”, “Hedgehog”, “APC”, “chromatin modification”, by the transcription factors Snail (SNAI1), Slug (SNAI2),
and “transcriptional regulation”contribute to cell fate ZEB1 (ZEB1), and ZEB2 (ZEB2). Expression of AID is
function. Genome maintenance is governed by “DNA induced by inflammatory signals that induce the EMT
damage control” [112] . The combined mutations-affected in nontransformed epithelial cells and in cancer cells.
critical molecules in the signalling pathway networks AID regulates expression of master regulators (SNAI1,
can be developed as novel diagnostic biomarkers and SNAI2, ZEB1, and ZEB2) in the EMT. Knockdown of
therapeutic targets. A series of somatic mutations AID blocks induction of the EMT and prevents cells from
in HBV-induced HCC mainly affect the chromatin acquiring invasive properties, suppresses expression
remodelling pathways (ARID1A, ARID1B, and ARID2), of several key EMT transcriptional regulators and is
the p53/RB tumor suppression pathway (IRF2, TP53, and associated with increased methylation of CpG islands
CDKN2A), the Wnt/β-catenin signal pathway (RPS6KA3- proximal to the promoters of SNAI1, SNAI2, ZEB1, and
AXIN1, NFE2L2-CTNNB1), and the Ras/PI3K pathway ZEB2 [122] . AID-mediated, CpG-methylation dependent
(PTEN, PIK3CA, KRAS, NRAS) [111,113-115] . Key genes mutagenesis is proven to be a common feature of
affecting epigenetic activities including ARID2, encoding carcinogenesis [123] . Thus, we have reasons to postulate
a subunit of the polybromo- and BRG1-associated factor that re-expression of embryonic factors in cancers
(PBAF) chromatin remodeling complex and ARID1A, as cancer biomarkers might result from epigenetic
encoding a component of the SWI/SNF chromatin reprogramming caused by AID/APOBECs, whose
remodeling complex are most frequent ones. In addition, expression is induced by proinflammatory factors.
cell invasion-related factors-coding genes VCAM1
and CDK14, and gene encoding androgen receptor AID/APOBECs promote tumor heterogeneity
(AR) [113,116] . Both C:G>A:T and T:A>A:T transversions are There are two kinds of tumor heterogeneity: intertumor
frequent among the non-silent mutations [114] , indicating heterogeneity and intratumor heterogeneity. First,
AID/APOBECs-induced somatic mutation is one of the patients with tumors of the same pathologic type show
major mutation patterns. These mutations facilitate the distinct clinical manifestations, including occurrence,
development of HCC via activating some evolutionarily metastasis, therapeutic response to chemo- and
conserved signal pathways, such as PI3K/Akt/mammalian radiation-therapies, and postoperative prognosis.
target of rapamycin, NF-κB/TNF-α, Raf/MAPK/ERK, This heterogeneity is the basis for the development
TGF-β1, Jak, Wnt/β-catenin, and STAT3/interleukin 6 (IL- of biomarkers and therapeutic targets that can predict
6) [117,118] , and also indicate that Wnt/β-catenin signaling cancer occurrence, metastasis, and therapeutic

252 Hepatoma Research ¦ Volume 3 ¦ October 27, 2017