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enzyme, which removes methyl- or alkyl-groups from in ESCC. [77,78] miR-375 is considered as ts-miR in several
guanidine after chemical modulation, therefore protecting cancers, including both histologic subtypes of esophageal
cells from G to A mutations. MLH1 and MSH2 are two cancer. [79,80] Reduced levels of miR-375 in cancerous
[58]
key DNA mismatch repair genes and epigenetic silencing tissue of EAC patients with Barrett’s were strongly
[80]
of these genes may lead to microsatellite instability. [59] associated with a worse prognosis. miR-205 was
down-regulated in both ESCC and EAC. [81,82] Knockdown
Promotors of APC, tissue inhibitor of metalloproteinases of miR-205 expression enhanced expression of zinc
3 (TIMP3), CDKN2A, CDH1, MGMT, DAPK, fi nger E-box homeobox 2, accompanied by a reduction
[60]
[61]
[62]
FHIT, AKAP12, and suppressors of cytokine of E-cadherin, leading to epithelial-mesenchymal
signaling (SOCS) have been reported to be frequently transition. miR-223 expression was signifi cantly higher
[63]
[82]
hypermethylated in EAC [Table 4]. TIMP3 belongs to a in ESCC with an inverse relationship with F-box and WD
family of genes that inhibit matrix metalloproteinases, a repeat domain-containing 7, a cell cycle regulatory gene
group of peptides involved in degeneration of extracellular whose protein product ubiquitinates cell cycle regulators
[64]
matrix. Death-associated protein kinase 1 is a positive such as c-Myc, cyclin E and c-jun. [83]
mediator of gamma-interferon-induced programmed cell
death. A-kinase anchoring protein 12 is a multivalent Recently, changes in expression of several miRs have
[65]
[84]
anchoring protein and an important regulator of the been reported in Barrett’s esophagus. miR expressions
beta2-adrenergic receptor complex. SOCS proteins act were compared between 2 groups of patients with
[62]
as negative regulators of JAK/STAT pathways and may Barrett’s esophagus who either developed or did not
[85]
represent tumor suppressors. Promotor methylation and develop EAC over a course of 5 years. As a result,
[66]
subsequent transcript down-regulation of SOCS-3 and 4 miRs (miR-192, miR-194, miR-196a, and miR-196b)
to a much lesser extent, SOCS-1 were involved in the were found to show signifi cantly higher expression in
multistep carcinogenesis of Barrett’s AC. [63] patients with progression to EAC than in those without.
Genome-wide DNA hypomethylation may also Conclusion
contribute to tumorigenesis. Long interspersed element
1 (LINE-1) is a retrotransposon comprising about In this review, the risk factors and molecular mechanisms
17% of the human genome, and the levels of LINE-1 of esophageal cancer, with special reference to the
methylation can be a surrogate marker of genome-wide differences between two histologic subtypes, have been
[54]
DNA methylation. Hypomethylation levels of LINE-1 discussed. In spite of advances in the diagnostic tools
are frequently observed in ESCC and correlate with and therapeutic strategies, esophageal cancer still remains
[67]
a poor prognosis. On the other hand, genome-wide one of the most lethal malignancies. In order to improve
methylation analysis also revealed that overall outcomes, early detection of tumors based on knowledge
methylation of CpG islands was higher, but outside of of risk factors is needed. In addition, efforts to identify
CpG islands was lower, in Barrett’s esophagus and EAC novel therapeutic targets through molecular biological
tissues than in normal esophageal tissues. [68] techniques are essential.
Histone modifi cations, including acetylation, methylation, References
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4 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 1 ¦ April 15, 2015 ¦