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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Am+J+Cancer+Res
2016 ; 6
(5
): 1066-77
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The aryl hydrocarbon receptor agonist benzo(a)pyrene reactivates LINE-1 in HepG2
cells through canonical TGF-?1 signaling: implications in hepatocellular
carcinogenesis
#MMPMID27293999
Reyes-Reyes EM
; Ramos IN
; Tavera-Garcia MA
; Ramos KS
Am J Cancer Res
2016[]; 6
(5
): 1066-77
PMID27293999
show ga
Long interspersed nuclear element-1 (L1) is a genetic element that mobilizes
throughout the mammalian genome via retrotransposition and damages host DNA via
mutational insertions, chromosomal rearrangements, and reprogramming of gene
expression. The cellular mechanisms responsible for aberrant L1 expression during
cancer pathogenesis are unclear. Previously, we have shown that L1 reactivation
in several human cell lines is dependent upon the activation of aryl hydrocarbon
receptor (AhR), a ligand-activated transcription factor member of the PAS
superfamily of proteins. We also showed that ectopic expression of L1 reprograms
the HepG2 genome leading to epithelial-to-mesenchymal transition (EMT). Here we
present evidence that reactivation of L1 and modulation of EMT in HepG2 cells by
the AhR ligand benzo(a)pyrene (BaP) is effected through the canonical TGF-?1
signaling pathway. BaP increased TGF-?1 mRNA, SMAD2 phosphorylation and decreased
expression of E-Cadherin. The functional relevance of these interactions and the
involvement of TGFBR1/ALK5 and SMAD2/3 were confirmed by siRNA interference.
Furthermore, expression of L1-encoded ORF1p was positively correlated with the
activation of TGF-?1 signaling in human hepatocarcinoma samples at various stages
of malignant progression. These results indicate that ligand-mediated AhR
activation regulates L1 via canonical TGF-?1 signaling and raise important
questions about the molecular etiology of human hepatocarcinomas.