MiR-21 upregulation increases IL8 expression and tumorigenesis program in airway epithelial cells exposed to cigarette smoke

Background: Cigarette smoke exposure, increasing Toll-like receptor 4 (TLR4) and
reactive oxygen species (ROS), promotes inflammatory responses in airway epithelial
cells. Chronic inflammation, microRNA (miRNA), and oxidative stress are associated
with cancer development.
Aims: The present study was aimed to explore whether cigarette smoke exposure,
altering miR-21 expression, promoted inflammatory responses and tumorigenesis
processes in airway epithelial cells.
Methods: Airway normal and cancer epithelial cells (16HBE and A549) were
exposed to cigarette smoke extracts (CSE) or with/without agomiR-21, and then
it was assessed: a) miR-21 expression; b) signal transducer and activator of
transcription 3 (STAT3) nuclear protein expression and ERK1/2 activation; c)
IL-8 gene expression and protein release. An antagonist of TLR4 (CLI-095) and
the antioxidant flavonoid, apigenin, were also included to evaluate miR-21
expression in CSE exposed cells.
Results: It was demonstrated that: a) A549 cells constitutively expressed higher
levels of miR-21 and IL-8; b) CSE increased STAT3 nuclear expression in 16HBE; c) in
both cell lines, CSE and agomiR-21 increased: miR-21 expression; ERK1/2 activation
and IL-8 gene expression and protein release; d) TLR4 inhibition counteracted the
effects of CSE on miR-21 in A549; e) apigenin reduced miR-21 and IL-8 gene
expression in both cell lines.
Conclusions: Data herein provided identified for the first time new mechanisms
supporting the crucial role of cigarette smoke-induced miR-21 expression in the
amplification of inflammatory responses and in tumorigenesis processes within the
airways.