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Cao Cancer Evo-Dev
subjects without HCC. Compared with HCC-free HBV- gives many other different types of cells via altering
infected subjects, rs2293152 GG is solely associated their gene expression profiling. The changes in gene
with HCC in women. This genotype is significantly expression profiling are achieved by epigenetic
associated with high viral load (≥ 1 × 10 copies/mL) modifications such as methylation in the upstream
4
and increased frequencies of T1674C/G and A1762T/ regulatory regions of given genes, rather than altering
G1764A. Multiplicative interaction of STAT3 rs1053004 the primary sequences of these genes. After born,
with T1674C/G significantly increases HCC risk, whereas lung takes over the responsibility of gas exchange,
rs2293152 and A1726C interaction reduces it, adjusting some genes only expressed in the embryonic stage
for covariates including HBV mutations in the EnhII/BCP/ are silenced and other genes solely expressed in adult
PreC region; the interaction of rs4796793 with preS2 cells are activated, most possibly by some epigenetic
start codon mutation significantly increases HCC risk, modifications. Surprisingly, the developmental process
adjusting for covariates including HBV mutations in the of humans resembles the process of long-term organic
preS region. Thus, STAT3 SNPs appear to predispose evolution morphologically, e.g. from single cell creatures
the host with HBV mutations to hepatocarcinogenesis [63] . to multicellular creatures, and from aquatic creatures and
We have also demonstrated that genetic polymorphisms amphibian to terrestrial mammals [Figure 3]. Furthermore,
improving NF-κB activity contribute to genotype B HBV some evolutionarily conserved molecular networks such
clearance. In the genotype C HBV-infected subjects, as HOX, Hedgehog, and Myc play important roles in the
variant genotypes of rs2233406 (NFKBIA-826C>T) are developmental process [66-72] , indicating development
significantly associated with an increased risk of HCC and evolution share some inherent mechanisms. During
compared with HCC-free HBV-infected subjects and the past 20 years, the discovery of conserved gene
significantly increase the frequencies of HCC-related networks that control embryonic development and the
HBV mutations including A1762T/G1764A, T1753V, ability to examine genomic records has revolutionized
preS1 start codon mutation, and preS deletion; Del Darwinian evolutionism that animal relationships had to
allele of rs28362491 (NFKB1-94Ins>Del) significantly be deduced by observation of external morphological
increase the frequency of A1762T/G1764A and reduce characteristics. The integration between developmental
the frequency of preS2 start codon mutation. The variant biology and evolution has been named Evo-Devo [73-77] .
genotypes impair NFKBIA promoter activity in hepatic Dr. Raff pointed out that the evolution of complex
cells. The interaction of rs2233406 variant genotypes organisms such as animals and plants had involved
(CT + TT vs. CC) with A1762T/G1764A significantly marked changes in morphology and new features had
increase the risk of HCC in genotype C HBV-infected appeared; but evolutionary change occurred not by
subjects [64,65] . These lines of evidence imply that the direct transformation of adult ancestors into adult
immunogenetic polymorphisms may predispose descendants but rather when developmental processes
chronic transformation of HBV infection, increase the produced the features of each generation in an
frequencies of viral mutations via activating cytosine evolving lineage. Thus, evolution cannot be understood
deaminases, and facilitate immune selection of HCC- if do not understand the evolution of development,
causing HBV mutations via arousing active but not and how the process of development itself biases
effective immune response against the pathogen. or constrains evolution [75] . Based on these previous
work, in combination with previous observations, I like
DEVELOPMENT AND EVOLUTION (DEV- to define Evo-Dev as follows: Evo-Dev is a discipline
to investigate the inherent mechanisms by which the
EVO), A NOVEL HYPOTHESIS RELATED TO short-term developmental process resembles the long-
CARCINOGENESIS term evolutionary process and to characterize the role
of developmental process on the evolution of complex
Development is referred to the process that a fertilized organisms.
egg develops into an individual. In humans, the fertilized
diploid cell composing of paternal haploid and maternal Carcinogenesis represents an evolutionary process.
haploid differentiates into various functional and/or It was firstly proposed by Dr. Nowell in 1976 that most
structural cells to form different organs and tissues neoplasms arise from a single cell of origin, and tumor
of an infant in mother’s uterus within 40 weeks. The progression results from acquired genetic variability
developmental process is a succession of functional within the original clone allowing sequential selection
and morphologic changes from a single cell form of more aggressive sublines; tumor cell populations
(fertilized egg) to a multicellular form (blastocyst), from are apparently more genetically unstable than normal
an aquatic state (living in amniotic fluid) to a terrestrial cells, perhaps from activation of specific gene loci in the
state (pulmonary respiration). During this process, the neoplasm [78] . Cancer clone genetic diversification and
founding diploid cell, a progenitor, divides rapidly and sub-clonal selection occurs within tissue ecosystems.
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