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2015 ; 36
(4
): 459-68
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Aberrantly expressed Fra-1 by IL-6/STAT3 transactivation promotes colorectal
cancer aggressiveness through epithelial-mesenchymal transition
#MMPMID25750173
Liu H
; Ren G
; Wang T
; Chen Y
; Gong C
; Bai Y
; Wang B
; Qi H
; Shen J
; Zhu L
; Qian C
; Lai M
; Shao J
Carcinogenesis
2015[Apr]; 36
(4
): 459-68
PMID25750173
show ga
The pro-inflammatory cytokine interleukin-6 (IL-6) in tumor microenvironment has
been suggested to promote development and progression of colorectal cancer (CRC).
However, the underlying molecular mechanisms remain elusive. In this study, we
demonstrate that fos-related antigen-1 (Fra-1) plays a critical role in IL-6
induced CRC aggressiveness and epithelial-mesenchymal transition (EMT). In CRC
cell lines, the expression of Fra-1 gene was found significantly upregulated
during IL-6-driven EMT process. The Fra-1 induction occurred at transcriptional
level in a manner dependent on signal transducer and activator of transcription 3
(STAT3), during which both phosphorylated and acetylated post-translational
modifications were required for STAT3 activation to directly bind to the Fra-1
promoter. Importantly, RNA interference-based attenuation of either STAT3 or
Fra-1 prevented IL-6-induced EMT, cell migration and invasion, whereas ectopic
expression of Fra-1 markedly reversed the STAT3-knockdown effect and enhanced CRC
cell aggressiveness by regulating the expression of EMT-promoting factors (ZEB1,
Snail, Slug, MMP-2 and MMP-9). Furthermore, Fra-1 levels were positively
correlated with the local invasion depth as well as lymph node and liver
metastasis in a total of 229 CRC patients. Intense immunohistochemical staining
of Fra-1 was observed at the tumor marginal area adjacent to inflammatory cells
and in parallel with IL-6 secretion and STAT3 activation in CRC tissues.
Together, this study proposes the existence of an aberrant IL-6/STAT3/Fra-1
signaling axis leading to CRC aggressiveness through EMT induction, which
suggests novel therapeutic opportunities for the malignant disease.
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